EP1310296A2 - Parallel semicontinuous or continuous reactors with a feed pressurization station - Google Patents

Abstract

A parallel, semi-continuous or continuous, pressure reactor comprising fouror more semi-continuous or continuous reaction vessels for containing a liquidreaction mixture, each of the four or more reaction vessels beingpressurizable to a pressure of not less than about 50 psig, at least four liquidfeed lines in selectable fluid communication with each of the four or morereaction vessels, each of the at least four liquid feed lines being in fluidcommunication with one or more liquid reagent source vessels, such that oneor more liquid reagents can be selectively fed from the one or more sourcevessels to each of the four or more reaction vessels during a reaction underreaction conditions, and. at least one feed-pressurization station pressurizableto a pressure of not less than about 50 psig, at least a portion of each of theat least four liquid feed lines being in selectable fluid communication with theat least one feed-pressurization station, such that the one or more liquidreagents prefeed to the feed-pressurization station under pressure toprepressurize the portion of the at least four liquid feed lines prior to feedingthe one or more liquid reagents to the four or more reaction vessels.

Description

The present invention is directed to parallel reactors, and in particular, toparallel research reactors suitable for use in a combinatorial (i.e., high-throughput)materials science research program. The invention is directed, in particular, to parallelsemicontinuous or continuous reactors, and in preferred embodiments, to parallelsemicontinuous or continuous stirred reactors. The invention is also directed tomethods of using such parallel reactors for synthesis and/or screening of materials orprocess conditions, to methods for synthesizing combinatorial libraries of materials,and to methods for screening combinatorial libraries of materials, such as catalysts.

Background

The present invention is related to the following co-owned, co-pending U.S.patent applications, each of which is hereby incorporated by reference for all purposes:U.S. Serial No. 60/255,716 filed December 14, 2000 by Safiret al. entitled "ParallelSemicontinuous or Continuous Stirred Reactors"; U.S. Serial No.60/209,142 filed June3, 2000 by Safiret al. entitled "Parallel Semicontinuous or Continuous StirredReactors"; U.S. Ser. No. 09/177,179 filed October 22, 1998 by Turneret al, entitled"Parallel Reactor with Internal Sensing and Method of Using Same"; U.S. Ser. No.09/211,982 filed December 14, 1998 by Turneret al., entitled "Improved ParallelReactor with Internal Sensing"; U.S. Ser. No. 09/548,848 filed April 13, 2000 byTurneret al, entitled "Parallel Reactor with Internal Sensing and Method of UsingSame"; U.S. Ser. No. 09/239,233 filed January 29, 1999 by Wanget al., entitled"Analysis and Control of Parallel Chemical Reactions"; U.S. Ser. No. 09/205,071 filedDecember 4, 1998 by Freitaget al., entitled "Continuous Feed Parallel Reactor"; U.S.Ser. No. 09/174,856 filed October 19, 1998 by Lacyet al., entitled "Graphic Design ofCombinatorial Material Libraries"; U.S. Ser. No. 09/420,334 filed October 18, 1999 byLacyet al., entitled "Graphic Design of Combinatorial Material Libraries"; and U.S.Ser. No. 09/305,830 filed May 5, 1999 by Rustet al., entitled "SynthesizingCombinatorial Libraries of Materials".

The aforementioned related applications disclose a number of embodiments forparallel research reactors suitable for use, for example, in combinatorial chemistryapplications such as polymer research and catalyst research.

In particular, U.S. applications Ser. No. 09/177,179, U.S. Ser. No. 09/211,982,and U.S. Ser. No. 09/548,848 applications disclose a parallel pressure reactor (PPR™)having modular parallel, stirred reactors with temperature and pressure control. U.S.Ser. No. 09/239,233 discloses methodologies and software for controlling such parallelreactors. Although such parallel reactors can be advantageously applied for manypolymer research applications (synthesis or screening of materials), the disclosedreactor systems have only limited capabilities for providing multiple reactants to thereaction vessel during the reaction.

Additionally, U.S. Ser. No. 09/205,071 discloses a parallel research reactor thatcan be adapted for semi-continuous (i.e., semi-batch) or continuous flow operation withone or more feed streams provided to each reactor. Although such a parallel reactorcan be advantageously applied for polymer research applications and other researchapplications requiring semicontinuous or continuous feed, improvements in thedisclosed multiple-feed capabilities are desirable, particularly with respect to higher-pressureapplications.

Other parallel synthesis reactors are known in the art, particularly inapplications directed toward the synthesis of biological polymers (e.g. nucleic acidpolymers such as oligonucleotides, or amino acid polymers such as peptides orproteins) or small organic molecules (e.g., having potential pharmaceutical ordiagnostic uses), and especially solid-phase synthesis of such compounds.See, forexample, U.S. Patent No. 5,746,982 to Saneiiet al., PCT patent application WO98/13137 of Antonenkoet al., European patent application EP 963 791 A2 of Harnesset al., PCT patent application WO 97/10896 of Mohanet al., PCT patent applicationWO 90/02605 of Meldalet al., European patent application EP 658 566 A1 ofChatelainet al., and U.S. Patent No. 5,792,431 to Mooreet al.. A system for paralleldissolution testing (e.g., for pharmaceutical compositions) is also known.See, forexample, European patent application EP 635 713 A1 of Hutchinset al.. These parallelresearch reactors and other instruments are not, however, generally useful forpolymerization research - typically involving higher temperatures, higher pressuresand/or in some cases, non-aqueous solvents. Moreover, such reactors have limited feedcapability during the reaction, and as such, are not generally adaptable for semi-continuousoperation with multiple feed streams.

In addition to the aforementioned limitations associated with particular designs,known parallel reactor designs generally suffer from common deficiencies -particularly with respect to applications for polymer research or other applications. Ingeneral, known designs are substantially limited with respect to operational flexibility,and do not generally offer higher numbers of feed lines per reactor in combination withdesirable higher pressures, higher temperatures, and effective stirring (forpolymerization reaction mixtures), in a semicontinuous or continuous operationalmode. In particular, the known reactor designs are spatially constrained, and offerlimited flexibility for incorporating larger number of feed lines to a relatively smallvolume reactors. Further, assembly and/or disassembly of the systems (e.g., for reactorvessel access) are relatively complicated, and would result in significant "down time"during an experimental cycle. Moreover, the known designs do not advantageouslyprovide the desired control of feed addition (e.g. feeding of precise, incrementalamounts of reagents) to the reaction vessel during a reaction under reaction conditions.Finally, the known parallel reactors offer only moderate flexibility, if any, with respectto evaluating process / protocol parameter space involving multiple reactants -including the sequence, total volume, rate, and temporal profile of reactant addition to areaction vessel.

Summary of the Invention

It is therefore an object of the present invention to overcome the deficiencies ofknown parallel reactors, and especially known parallel research reactors. In particular,it is an object of the invention to provide apparatus, methodologies, and software (orfirmware) that will enable a research scientist to effect simultaneous reactions in aparallel reactor system having multiple feeds, with efficient stirring for polymerizationreaction mixtures and with substantial flexibility for feed configuration, reactionconditions, and feed-protocols.

Briefly, therefore, the present invention is directed, in one embodiment, to aparallel reactor, and especially to a parallel research reactor suitably configured foroperation in semi-continuous or continuous mode. The parallel reactor comprises twoor more, preferably four or more reaction vessels for containing liquid reactionmixtures. Each of the two or more (or four or more) reaction vessels can have a volumeof not more than about 1 liter, preferably not more than about 500 ml, and is pressurizable to a pressure of not less than about 50 psig (i.e., is hermetically sealed),preferably not less than about 100 psig, preferably not less than about 1000 psig.Although pressurizable to higher pressures, the apparatus has significant applications atatmospheric pressure. The two or more, and preferably four or more reaction vesselsare preferably integral with (e.g. formed or otherwise contained in) a common reactorblock. In some embodiments, however(e.g., with volumes of not more than about 1liter), the reaction vessels can be configured independently of each other (e.g. withoutbeing formed in a common reactor block). Two or more (or four or more) shaft-drivenstirrers(e.g., shaft-driven impellers) can be provided for stirring the reaction mixtures.The shaft-driven stirrers (e.g. impellers) are, if provided, preferably arranged tocorrespond to the arrangement of the two or more (or four or more) reaction vessels.The reactor vessel further comprises at least two, preferably at least three, and morepreferably at least four feed lines(e.g., liquid feed lines) in fluid communication witheach of the two or more (or four or more) reaction vessels. Each of the at least three (orat least four) feed lines provide fluid communication, preferably selective fluidcommunication, between the reaction vessel and one or more reagent sources (e.g.liquid reagent sources).

In preferred embodiments, the invention is directed to a parallel reactor(e.g., asdescribed in the preceding paragraph), or to a reactor having a single reaction vessel, ineither case configured for semi-continuous or continuous operation, that includescertain features (considered independently, in combination with the above embodiment,and/or in various combinations with each other) that enhance the functionality orefficiency of a multi-feed system, and/or that improve the control of feed addition tothe reaction vessel(s). Briefly, such features include, without limitation, a feed-pressurizationstation (e.g., pressurized waste vessel), one or more modular feed-linesubassemblies(e.g. ferrules), capillary-type feed lines, multi-section (e.g., two-section)feed lines, multiple feed lines with independently and differently-positioned distal ends,feed lines with independently and differently-varied feed-line sizes, disposable shaft-coversand/or disposable header block gaskets for masking at least non-disposableportions of the shafts or header that are exposed within the reaction cavity and/orspecific feed distribution system designs, including especially feed distribution systemsin which one or more source vessels are multiplexed through a single pump (e.g.,syringe pump) and one or more selection valves (e.g., feed distribution valves), to each of multiple feed lines serving multiple reaction vessels. Such features are brieflysummarized in more detail as follows, and further described below.

In one such preferred embodiment, a feed-pressurization station (e.g.,pressurized waste vessel) is in selectable fluid communication with the feed line(s) suchthat the feed line(s) can be prepressurized - prior to feeding reagents to the reactionvessel(s) - by prefeeding the liquid reagent(s) to the feed-pressurization station underpressure, preferably under pressure that is substantially the same as the reactionpressure.

In another such embodiment, for example, the invention includes one or moremodular feed-line subassemblies (e.g. ferrules), with each of the feed-linesubassemblies being adapted to releasably engage a reaction vessel or a reactor blockhaving a reaction cavity that defines or contains the reaction vessel. The feed-linesubassembly supports at least two feed lines (and preferably at least three or at leastfour feed lines) passing into the reaction vessel through a feed-line subassemblyreceiving port that is formed in the reaction vessel or the reactor block.

In an additional such embodiment, the feed lines are capillary feed lines (e.g.,glass (e.g., fused silica) capillaries, stainless-steel capillaries and/or polymer (e.g.teflon) capillaries).

In another such embodiment, one of, or preferably each of, the at least two, atleast three (or at least four) liquid feed lines are multi-section feed lines, having at leasta first section and a second section in fluid communication with each other. Preferably,the second section is releasably engaged with the first section and has a distal endpositioned within the reaction vessel or within a reaction cavity or reaction chamberthat defines or contains the reaction vessel.

In an additional such embodiment, each of the at least two, at least three (or atleast four) liquid feed lines has a distal end positioned within the reaction vessel, andthe distal end of one or more of the feed lines (i.e., a first subset of the feed lines) ispositioned lower in the reaction vessel relative to the distal end of one or more other ofthe feed lines (i.e., a second subset of the feed lines). Such an approach is particularlyadvantageous with respect to delivery of some of the reagents directly into the a liquidreaction mixture and some other reagents into a gaseous headspace above the liquidreaction mixture.

In a further such embodiment, each of the at least two, at least three (or at leastfour) liquid feed lines has an inside diameter or cross-sectional flow area, and one ormore of the at least three (or at least four) liquid feed lines (i.e., a first subset of the feedlines) has an inside diameter or cross-sectional flow area that differs from the insidediameter or cross-sectional flow area for another of the at least four liquid feed lines(i.e., a second subset of the feed lines).

In yet a further such embodiment, the various components within the reactioncavity that are exposed to the reaction conditions are either disposable (e.g. disposablevials as reaction vessels, disposable feed-line sections, disposable impellers) and/or aremasked from the reaction environment by gaskets (e.g. header gasket having maskingregions) covers (e.g., shaft covers) or other masking materials - with such maskingmaterials themselves being disposable.

The invention is likewise directed to methods for using the any of theaforementioned apparatus to effect multi-feed chemical reactions in parallel - generallyby feeding three or more (or four or more) liquid reagents through the three or more (orfour or more) feed lines to each of the two or more (or four or more) reactors during thecourse of a reaction.

The invention is directed as well to methods for effecting multi-feed chemicalreactions in parallel. In general, the methods include providing one or more of theaforementioned single and/or parallel reactors, and feeding, preferably selectivelyfeeding, one or more liquid reagents through the one or more (e.g., two or more, threeor more, four or more,etc.) feed lines to the reaction vessel(s) during a reaction underreaction conditions, preferably under reaction conditions that include a reactionpressure of not less than about 50 psig.

In one preferred embodiment, a parallel pressure reactor is provided. Theparallel pressure reactor comprises two or more, preferably four or more semi-continuousor continuous reaction vessels, one or more liquid reagent source vessels,and at least two, preferably four liquid feed lines providing selectable fluidcommunication between the one or more liquid reagent source vessels and the four ormore reaction vessels. A chemical reaction is initiated in each of the four or morereaction vessels under reaction conditions that include a reaction pressure of not lessthan about 50 psig. One or more liquid reagents are prefed through one or more of theat least four feed lines to a feed-pressurization zone- preferably a pressurized waste vessel. The feed-pressurization zone is maintained at a pressure of not less than about50 psig, and preferably at a pressure that corresponds substantially to the reactionpressure, such that the feed lines contain prepressurized liquid reagent feed. Theprepressurized liquid reagent feed is then subsequently fed into one or more of the twoor more, or four or more reactor vessels during the reaction under the reactionconditions.

Additionally, and generally, such methods are preferably implemented withuser-directed reactor-control software or firmware incorporated with the reactor,together with a graphical user interface. The feed control effected, preferably with suchsoftware or firmware; is preferably applied in connection with methods in which aparallel reactor is provided and comprises four or more semi-continuous or continuousreaction vessels, four or more liquid reagent source vessels, and at least four liquid feedlines providing selectable fluid communication between the four or more liquid reagentsource vessels and the four or more reaction vessels. A chemical reaction is initiated ineach of the four or more reaction vessels under reaction conditions, and the four ormore liquid reagents are fed into the four or more reaction vessels during the reactionunder the reaction conditions. Significantly, the feed control, for each of the reactionvessels, can include controlling (e.g., specifying and/or directing) (i) a total volume ofeach of the liquid reagents being fed to the reaction vessel during the reaction, the totalvolume being the same or different as compared between different reagents, (ii) anumber of stages in which the total volume for each of the liquid reagents are fed to thereaction vessel during the reaction, the number of stages being the same or different ascompared between different reagents, (iii) a stage volume defined by a percentage ofthe total volume associated with each of the stages for each of the liquid reagents, thestage volume being the same or different as compared between different stages for eachof the liquid reagents, (iv) a feed sequence defined by a relative order in which thestages for each of the liquid reagents are fed to the reaction vessel during the reaction,and (v) a temporal profile associated with feed addition to the reaction vessel for eachof the stages for each of the liquid reagents, the temporal profile being defined for eachstage by a number of feed increments in which the stage volume is added to thereaction vessel, and the period of time in which the stage volume is added to thereaction vessel.

The feed addition is preferably controlled, as considered between reactionvessels, sequentially, on a rotating basis, for each of the four or more reaction vesselsduring the reaction by (i) considering and providing the feed requirements for a firstreaction vessel at a first time after initiation of the chemical reaction therein, andthereafter, (ii) by considering and providing the feed requirements for a second reactionvessel at a second time after initiation of the chemical reaction therein, and thereafter,(iii) by considering and providing the feed requirements for a third reaction vessel at athird time after initiation of the chemical reaction therein, and thereafter, (iv) byconsidering and providing the feed requirements for a fourth reaction vessel at a fourthtime after initiation of the chemical reaction therein.

Advantageously, the present invention overcomes many deficiencies of the priorart. In particular, the multiple-feed reactors of the present invention offer substantialsimplicity in design, and afford efficient, effective assembly and disassembly for accessto the reaction vessel(s). Moreover, unique design features enable a multiple feedconfiguration suitable for spatially constrained reactors- such as relatively smallvolume reactors having shaft-driven stirring- even for relatively higher numbers offeed lines per reactor. The instant inventions also provide substantial flexibility andcontrol over the nature of the feed addition to the reaction vessel. Furthermore, theparallel reactors disclosed herein are especially advantageous with respect toapplications involving evaluation of process / protocol parameter space involvingmultiple reactants - including without limitation, the sequence, total volume, rate, andtemporal profile of reactant addition to a reaction vessel, together with temperatureprofiles and/or pressure profiles.

Other features, objects and advantages of the present invention will be in partapparent to those skilled in art and in part pointed out hereinafter. All references citedin the instant specification are incorporated by reference for all purposes. Moreover, asthe patent and non-patent literature relating to the subject matter disclosed and/orclaimed herein is substantial, many relevant references are available to a skilled artisanthat will provide further instruction with respect to such subject matter.

The invention is described in further detail below with reference to the attachedfigures, in which like items are numbered the same in the several figures.

Detailed Description of the Invention

Although described herein primarily in connection with applications involvingchemical reactions, the reaction system can be a more general chemical processingsystem suitable for use with other chemical operations, that may not necessarily involvethe making or breaking of a chemical bond. Such other applications, include, forexample, the preparation of formulations, blending operations, and crystallizationoperations(e.g., for combinatorial investigations of polymorphic crystalline structures,among other applications).

Overview

The parallel reactor system of the present invention provides for asemicontinuous flow regime, or in an alternative embodiment, a continuous flowregime, for a number ("n", where n ≥ 2, and preferably n ≥ 4) of reaction vesselsconfigured for parallel operation (e.g., configured for operation with at least foursimultaneous reactions in at least four different reaction vessels, and ranging from fourto "n" simultaneous reactions in from four to "n" different reaction vessels,respectively).

In a semicontinuous flow embodiment, with reference to Figure 1A, a number("N", where N ≥ 2) offeed lines 300 are provided to each of the n reaction vessels(represented schematically in Figure 1 as a collective group of reaction vessels [R₁, R₂,R₃, R₄, R₅, R₆, R₇, R₈.... R_n] and indicated generally as 500) such that each of Nreagents can be added (e.g. intermittently) to each of then reaction vessels 500 duringthe course of the reactions occurring in each of then reaction vessels 500. A feeddistribution system comprising theN feed lines 300 provides fluid communicationbetween each of N different reagent source vessels 100 (labeled schematically in Figure1A as SV₁ through SV_N) and each of then reaction vessels 500, typically through Ndedicated pumps 200. In the semicontinuous embodiment, then reaction vessels 500are semi-batch reactors lacking a continuous discharge line (or alternatively, at leastoperated as semi-batch reactor, for example, with a discharge line valved shut,optionally except for intermittent sampling), such that substantially none of the reactionmixture is discharged from the reaction vessel during the course of the reaction.

In a continuous flow embodiment, with reference again to Figure 1A, a number("N", where N ≥ 2) offeed lines 300 are provided to each of the n reaction vessels (represented schematically in Figure 1 as a collective group of reaction vessels [R₁, R₂,R₃, R₄, R₅, R₆, R₇, R₈.... R_n] and indicated generally as 500) such that each of Nreagents can be added (e.g., intermittently) to each of then reaction vessels 500 duringthe course of the reactions occurring in each of then reaction vessels 500. A feeddistribution system comprising theN feed lines 300 provides fluid communicationbetween each of N different reagent source vessels 100 (labeled schematically in Figure1A as SV₁ through SV_N) and each of then reaction vessels 500, typically through Ndedicated pumps 200. In the continuous embodiment, then reaction vessels 500 arecontinuous-flow reactors and a discharge distribution system provides fluidcommunication between each of the n reaction vessels is and at least onedischarge line600 such that at least a portion of the reaction mixture can be discharged (e.g.,intermittently) from each of the n reaction vessels during the course of the reactions(e.g., to a common or to separate collection receptacle (e.g., waste receptacle) and/or asample line).

In operation, in the semicontinuous flow or the continuous flow embodiments,the reagents from the Nreagent source vessels 100 can be fed, throughfeed lines 300,to the n reaction vessels during the course of the reaction. The duration of feed canvary, and can be continuous over a period of time (i.e., temporally continuous) orintermittent over a period of time (i.e., temporally intermittent). In the continuous flowembodiment, a portion of the reaction mixture can be discharged from the reactionvessel during the course of the reaction, with the period of discharge varying induration. The duration of the discharge can be temporally continuous, or temporallyintermittent, and in some applications, can be temporally synchronized with the feedingof reagents (e.g. for operation as a continuous reactor, such as a continuous stirred tankreactor).

The number of reaction vessels and/or reagent source vessels (with associateddedicated feed channels) can vary for the parallel reactor system of the presentinvention. As noted above, the number of reaction vessels can be two or more, but ispreferably at least about 4 and is more preferably about 8 or more reaction vessels.Higher numbers, n, of reaction vessels can be employed, including for example, 16 ormore, 40 or more, 60 or more, 100 or more, 400 or more or 1000 or more. In someembodiments, the number of reaction vessels can be at least about 96*M, whereMranges from 1 to about 100, and preferably ranges from 1 to about 10, and most preferably ranges from 1 to about 5. The 4 or more reaction vessels can beindependently positioned with respect to each other, or alternatively, can be formed inmodules or in a monolith. The number, N, of feed channels associated with each of then reaction vessels can, as noted above, be at least about 2, and in some embodiments, ispreferably 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, or 8 or more, and canrange, for example, from 2 to about 20, preferably from 2 to about 10, more preferablyfrom 3 to about 10, and most preferably from 4 to about 8.

The correspondence between the four or more reaction vessels and the two ormore feed streams can be complete or, particularly with higher numbers of reactionvessels, n, and higher numbers of feed channels, N, such correspondence can be partial.With reference to Figure 1B, for example, each of the N feed channels (indicated as Nreagent source vessel, SV's) can be in independent fluid communication with each ofthe n reaction vessels. Alternatively, with reference to Figure 1C, for example, varioussubsets of the N feed channels (each of the various subsets comprising at least 2 reagentsource vessels and reagent feed channels) can be in independent fluid communicationwith various subsets of the n reaction vessels (each of the various subsets comprising atleast four reaction vessels). The particular correspondence will be apparent to a personof skill in the art in view of the chemistry of interest being applied in the parallelreactor. Advantageously, in preferred embodiments, the parallel semicontinuous orcontinuous reactor of the present invention can be flexibly configured to have a firstfeed channel - reaction vessel correspondence, and then reconfigured to have a secondfeed channel - reaction vessel correspondence, completely by appropriate control ofdistribution valving included as part of the feed distribution system.

Feed Distribution Systems

The feed distribution system for either of the aforementioned semicontinuousembodiment or continuous embodiment can include a feed-line splitting arrangement ora feed-line valving arrangement that provides for fluid communication, preferablyselectable fluid communication, between one of the reagent source vessels (e.g., SV_N)and each of the n reaction vessels.

In a preferred feed distribution system, shown schematically in Figure 2A,selective fluid communication between one of thereagent source vessels 100 and the nreaction vessels is selectively provided through a selection valve, designated herein as afeed distribution valve 400. Hence in operation, one of the N reagents is pumped by adedicated distribution pump 200 from thereagent source vessel 100 through acommonfeed line 300 to afeed inlet 410 of thefeed distribution valve 400. Thefeed distributionvalve 400 is controlled (e.g., with microprocessor 1000) to selectively provide fluidcommunication between thefeed inlet 410 and one (or more) ofn feed outlets 420.Feed lines 300' provide fluid communication between each of then feed outlets 420and one of then reaction vessels 500. Alternatively, where additional feed-branching isrequired (e.g., where n is sufficiently high), each of the feed lines 300' couldthemselves be in fluid communication with an additional selection valve (not shown),the outlets of which could be in fluid communication with the reaction vessels. One ofthe feed outlets 420' of thefeed distribution valve 400 can be in fluid communicationwith a rinse collection vessel (e.g., for flushing the distribution valve), or alternatively arinse source vessel. Although details of the feed distribution system as shown in Figure2A are depicted only for one of the N reagent feed channels (to each of the n reactors),each of the other reagent feed channels could be likewise configured with a selectionvalve (See Figure 2B).

An alternative feed distribution system, shown schematically in Figure 2C,includes a plurality of separatemulti-way valves 430 in place of the single, feed-linedistribution valve. Reagent feed is fed from thereagent source vessel 100 through apump 200 through acommon feed line 300 to afeed inlet 410 of themulti-way valve430. The mutil-valves 430 are each controlled (e.g., with a microprocessor, not shown)to selectively provide fluid communication between thefeed inlet 410 and either afeedoutlet 420 or abypass outlet 415. Thebypass outlet 415 of the last valve in the seriescan be capped. Feed lines 300' provide fluid communication between each of thenfeed outlets 420 and one of then reaction vessels 500.

In operation, the preferred feed distribution system (comprising at least one feeddistribution valve for each of the N feed channels and having adedicated distributionpump 200 associated with each reagent source vessel, as discussed in connection withFig. 2A and Fig. 2B) or the alternative feed distribution system (discussed inconnection with Fig. 2C) each offer substantial flexibility with respect to the addition offrom two to N reagents to the n reaction vessels. For example, first and secondreagents, reagent feeds 1 and 2, respectively, can be supplied simultaneously from theirrespective first and second reagent source vessels (SV1, SV2) to the same reaction vessel (e.g., R₃). Alternatively, the first and second reagents can be supplied atdifferent times to the same reaction vessel. The same flexibility exists for each of theother reaction vessels. Hence, substantial operational flexibility is achieved withrespect to control of reagent feed timing to one of the parallel reaction vessels.Moreover, such flexible control is achieved, independently, with respect to each of theother n reaction vessels.

Additionally, because each of the reagent feed channels preferably has its owndedicated distribution pump, and because each channel can be selectively fed to any ofthe n reactors, the aforementioned feed distribution systems advantageously provide forindependently controlled rates of feed addition (for each reagent to each of the nreactors). Such control can be particular advantageous for combinatorial chemistryapplications, in which feed rates and/or timing can affect the reaction in progress.

In some cases, or for some reagent source vessels, it may nonetheless beadvantageous to have one or more non-dedicated distribution pumps - that is, one ormore pumps that service a plurality of different reagent source vessels (rather thanhaving dedicated association with one reagent source vessel). With reference to Figure2E, for example, asingle pump 200 such as a syringe-type pump can service a pluralityofreagent source vessels 100 by aligning the pump with one or the other of thesourcevessels 100 through a selection valve. The selection valve can be in-line on the inletside of a flow-through pump (not shown), or alternatively, as shown in Figure 2E, theselection valve can be afeed distribution valve 400 for pumps such as syringe-typepumps that have temporally separate intake and output modes. In operation for thelatter case, the reagent in the alignedsource vessel 100 can be taken up in the pumpreservoir during the intake mode, and then discharged to the appropriate feed line 300'(i.e., to R₁, R₂,... R_n) through thedistribution valve 400 during the output mode.Although not shown in Figure 2E, a similar configuration can be used to align aplurality ofpumps 200 to one ormore source vessels 100 through a common selectionvalve, such asdistribution valve 400.

The feed distribution system preferably comprises separate dedicated feedchannels for each of the N reagent feeds, where the feed channels are completely (or atleast substantially) independent of each other, such that no substantial mixing of thefeed streams occurs prior to being fed into the reactor. Such a configurationadvantageously allows for delivery of different reagents to a particular reaction vessel where the reagents being added are chemically incompatible with each other (e.g.,would react with each other if mixed prior to addition to the reaction vessel).Moreover, such a configuration also allows for delivery of reagents that would form aheterogeneous (i.e., two-phase) mixture if combined before delivery. If the two-phasemixture were non-uniform, the actual amount of each phase delivered to a reactionvessel would be difficult to control.

For chemical reaction applications where reagent compatibility and phasehomogeneity between at least two reagents is not a substantial concern, an embodimentallowing for at least some pre-mixing of the at least two reagents can be effected. Thereagents can be premixed, for example, in a mixing vessel (preferably comprising anactive mixing element), and the mixture can then be distributed as a mixed-feed streamto the reaction vessel of interest. In an alternative pre-mixing approach, shownschematically in Figure 2D, premixing can be effected "in-line" in acommon feed line310". Thefeed line 310 can be a passive mixer (e.g., comprising a tortuous mixingpath). As depicted, the feed distribution system includes a plurality of separatemulti-waymixing valves 440. Reagent feed is fed from the variousreagent source vessels100 throughpumps 200 andfeed lines 300 to afeed inlet 410 of themulti-way mixingvalve 440. Themulti-way mixing valves 440 are each controlled(e.g., with amicroprocessor, not shown) to selectively provide fluid communication between theone ormore feed inlets 410 and a mixed-feed outlet 417 or alternatively, abypass outlet415. The mixed-feed outlet 417 of the last valve in the series is also thefeed outlet 420for the series of valves.

Fluid communication between reagent source vessels (e.g., SV_N) and some oreach of the n reaction vessels can, in general, be provided by any suitable approach, andthe aforementioned embodiments are to be considered exemplary and non-limiting.

Another non-limiting, exemplary distribution system can provide reagentdistribution from each of eight reagent source vessels (as well as a ninth rinse vessel) toeach of eight reaction vessels through eight (or nine) dedicated pumps, five non-dedicateddistribution valves, and five non-dedicated feed lines, as follows, withreference to Figure 2F. A first reagent source vessel (SV1) can be aligned to a firstdedicated feed line (LINE 1) for each of the eight reaction vessels through a dedicatedfirst distribution pump (PUMP 1) and a first feed distribution valve (VALVE 1).Likewise, second and third reagent source vessels (SV2, SV3) can be aligned to dedicated second and third feed lines, respectively (LINE 2, LINE 3) for each of theeight reaction vessels through dedicated second and third distribution pumps,respectively (PUMP 2, PUMP 3) and second and third feed distribution valves, .respectively (VALVE 2, VALVE 3). A fourth reagent source vessel (SV4) and a fifthreagent source vessel (SV5), can each be aligned to the same common fourth feed line(LINE 4) through separate dedicated fourth and fifth pumps, respectively (PUMP 4,PUMP5), and a common non-dedicated feed distribution valve (VALVE 4). Similarly,each of a sixth, seventh and eighth source vessel, optionally together with a ninth rinsevessel (SV6, SV7, SV8, SV9), can each be aligned to the same common non-dedicatedfifth feed line (LINE 5) through separate dedicated sixth, seventh, eighth and ninthpumps, respectively, (PUMP 6, PUMP7, PUMP8, PUMP9), and a common non-dedicatedfeed distribution valve (VALVE 5). Such a feed distribution scheme strikes abalance between total operational flexibility (since some reagent source vessels sharesome feed lines) and cost (e.g. especially costs associated with distribution valves).

A further non-limiting, exemplary distribution system can provide completelydedicated reagent distribution from each of eight reagent source vessels (as well as aninth rinse vessel) to each of eight reaction vessels through eight dedicated distributionpumps, eight dedicated distribution valves, and eight dedicated feed lines, as follows.Briefly, with reference to Figure 2G, first through eighth reagent source vessels (SV1through SV8) can be aligned to dedicated first through eighth feed lines, respectively(LINE 1 through LINE 8) for each of the eight reaction vessels through dedicated firstthrough eighth distribution pumps, respectively (PUMP 1 through PUMP 8) and firstthrough eighth dedicated feed distribution valves, respectively (VALVE 1 throughVALVE 8). Such a feed distribution scheme is preferred with respect to maximumoperational flexibility.

Regardless of the particular distribution system configuration, it may be usefulat higher pressures and with certain types of pumps (e.g. syringe pumps) to provide atleast one feed-pressurization station pressurizable to a pressure of not less than about50 psig, with which each of the at least two (or at least three, preferably at least four)liquid feed lines (or at least a portion thereof) can be in selectable fluid communication- such that the feed lines can prefeed the one or more liquid reagents to the feed-pressurizationstation under pressure to prepressurize the four feed lines (or at least aportion thereof) prior to feeding the one or more liquid reagents to the four or more reaction vessels. The feed-pressurization station can, in especially preferredembodiments, also function as a waste vessel, for collection of waste feed. Withreference to Figure 2E, for example, a feed-pressurization station 1205 is provided withan appropriate pressure-control system. The feed-pressurization station 1205 is inselectable fluid communication withfeed line 300 throughdistribution valve 400 andappropriate conduits and optionally, additional valving. The feed-pressurization station1205 can be any pressurized zone, but is depicted in Figure 2E as comprising a liquidspace and a gaseous headspace, with pressure in the pressure chamber being maintainedat or near the desired system operating pressure. In operation, a reagent in one of thealignedsource vessels 100 can be taken up in the pump reservoir during the intakemode of the pumping cycle, and then discharged throughfeed line 300 and thedistribution valve 400, which is selected to the feed-pressurization station 1205,maintained at the desired pressure. Advantageously, prefeeding the one or more liquidreagents to the feed-pressurization station under pressure allows the upstream portionof the feed distribution system (feed line 300) to contain prepressurized liquid reagentfeed - thereby minimizing feed-addition errors that would otherwise (i.e., in theabsence of such pre-pressurizing) arise due to compressibility of the liquid reagent, andin some cases, due to pressure-induced expansion of the feed line (e.g., when the feedline is a non-rigid, expandable material, such as Teflon or other non-rigid polymers).Such errors could be appreciable in smaller-scale systems and/or where exactingcontrol over total volume of feed addition or feed rates are important for the reaction ofinterest. Subsequently, the prepressurized liquid reagent feed infeed line 300 can thenbe fed into one or more of thereactor vessels 500 during the reaction under the reactionconditions through distribution valve 400 (selected to the particular reaction vessel 500)and downstream feed line 300' (such down-stream feed line 300' already being at thereaction pressure, for example, in systems without the check valve shown in feed line300'). In a preferred operational embodiment, the pressure in the feed-pressurizationstation 1205 (e.g., pressurized waste vessel) can be substantially the same as thepressure in thereaction vessel 500 to which the feed will be delivered (i.e., at reactionpressure for feed delivered during the reaction under reaction conditions). In otheroperation embodiments, however, the pressure can be different from the pressure in theassociatedreaction vessel 500, and still provide for at least some of the aforementionedbenefits. In some configurations, there may be two or more, three or more or four or more pressurization stations (e.g., corresponding to the number of feed pumps, or to thenumber of distribution valves or to the number of reactors).

Additionally, and regardless of the particular distribution system configuration,it may also be useful at higher pressures and with certain types of pumps (e.g. syringepumps) to provide a pressure chamber to absorb and attenuate fluctuations in pressurein the system that are associated with pump start-ups, pump-mode shifts (e.g., fromintake mode to output mode) or other pressure-pertubation-causing events. Withreference to Figure 2E, for example, apressure chamber 1200 can be provided withappropriate varying and conduits to provide fluid communication with each of thereaction vessels 500. Thepressure chamber 1200 can comprise a liquid space and agaseous headspace, with pressure in the pressure chamber being maintained at or nearthe desired system operating pressure.

As discussed in greater detail below, in addition to the three or more liquid feedlines, each of the two or more (preferably four or more) reaction vessels can compriseone or more gas ports providing fluid communication between the reaction vessel andone or more external requirements, such as one or more gaseous sources(e.g., forfeeding gaseous reactants to the reaction vessel, for purging the reaction vessel with aninert gas, and/or for controlling reaction pressure), or one or more pressure sensors formonitoring and/or controlling reaction pressure. Gaseous delivery can be effected byconventional means known in the art. For operating at higher pressures (e.g., atpressures equal to or greater than the pre-pressure of gaseous reactant tanks ascommercially available), it may be advantageous to include pressure-boostingequipment within the fluid distribution system. With reference to Figure 2E, forexample, a pre-pressurizer 1210 (operating roughly analogous to an accumulator) canbe used to prepressurize a reactant gas(e.g. loaded from a gas source vessel 1220 atlower pressures into afirst gas space 1211 on a first side of a piston 1212) using aninert gas available at higher pressures (e.g. and loaded at higher pressures into a secondgas space 1213 on a second side of a piston 1212).

The pumps employed in the present parallel reactor system are preferablypositive displacement pumps, and are preferably adapted for small volume increments.Pump control, and step size are important further considerations. Exemplary pumpsinclude syringe pumps, and other pumps generally disclosed in the aforementionedrelated patent applications. Digitally-controlled syringe pumps are particularly well suited to the present invention, and can add the desired volume using from about 3000to about 12,000 increments of the total volume.

Discharge Distribution System

The discharge distribution system for any of the aforementionedsemicontinuous embodiments or continuous embodiments can provide.fluidcommunication between the reaction vessel and a waste reservoir, a sampling system(e.g., for characterization of a sample taken from the reaction mixture, and/or anotherreaction system (e.g. for feed to a second reaction vessel in a series). As shown inFigures 2A through 2D, for example, the discharge distribution system can comprise adischarge valve 700 or sampling valve (also 700) that provides selective fluidcommunication between thedischarge line 600 and one of a waste collection system, asample analysis system, a second reaction system, and/or another system. Althoughshown in Figures 2A through 2D with only asingle discharge line 600, eachreactionvessel 500 could alternatively have two or more discharge lines (for sampling and/orwaste).

It is also contemplated that a feed distribution line could also be used as adischarge line (e.g., by reversing the direction of the pump). In one embodiment, forexample, one or more of the 8 liquid feed systems can be run in "reverse" to samplealiquots of the reaction mixture from each vessel, for reaction monitoring or off-lineanalysis. In this case it may be especially desirable to have additional valves connectedto the distribution manifold to allow for sample collection, flushing or washing of thesyringe, lines, or valves, or expelling excess reagent to a waste-collection vessel. Itmay also be desirable to connect one or more input lines supplying each syringe toeither a distribution valve to select multiple reagent feeds to one distribution channel, orto an XYZ robotic probe that can select multiple sources. Similarly, the output linesfrom one or more of the valves may be connected to a distribution valve or to an XYZrobotic probe to enable delivery of aliquots sampled from the reactor vessels todifferent sample containers.

Reaction Vessels

The reaction vessels are preferably chemically inert. A reaction vessel can beformed in a material that provides structural support(e.g, stainless steel) or can be a vial or liner within another structure. Various general configurations for the reactionvessels are described in the aforementioned related U.S. patent applications and areexpressly incorporated herein by reference. The reaction vessel is preferably a researchreactor vessel, but could also be a relatively small-volume production vessel.

In a preferred embodiment, two or more (preferably four or more) reactionvessels are provided in a reactor block. The reactor block can include two or more(preferably four or more) reaction cavities, each having an interior surface that definesor contains a reaction vessel. Hence, the two or more (or four or more) reaction vesselscan be wells formed in the reactor block, or alternatively, can be removable linerssupported by wells formed in the reactor block. Such liners have an interior surfacedefining a cavity for containing a liquid reaction mixture, and an external surfacedimensioned so that the liner fits within the wells.

Referring to Figures 4A through 4H, areactor block 520 can comprise abaseblock 530 and aheader block 540. Areaction vessel 500 of the present invention cancomprise aninner surface 505 at least partially formed in thebase block 530. Theinnersurface 505 can additionally, or alternatively definc at least a portion of a reactioncavity or, equivalently, areaction chamber 510, that forms the pressure boundaryaround each reaction vessel, when considered with appropriate seals,etc. Thereactioncavity 510 can contain a reaction vessel 500 (Fig. 4G) such as a removable liner (e.g.glass vial). Theinner surface 505 can be formed in thebase block 530 as two or more(or four or more) wells 532 (Fig. 4G) that define or contain thereaction vessels 500, oras through-holes 534 (Fig. 4B) with associatedbottom plate 533. Theheader block540 can be removably positioned (e.g., secured through non-permanent fasteners suchas bolts or latches, not shown) over thebase block 530 such that it provides access tothe reaction vessels 500 (when removed) and such that it forms two or more (preferablyfour or more) pressurizable reaction cavities or chambers 510 (when secured inposition). One or more seals, such as individual o-ring type seals 535 can be positionedbetween thebase block 530 and theheader block 540 ingrooves 536 formed in thebaseblock 530 and/or theheader block 540 to individually seal each of the two or more(preferably four or more) reaction cavities orchambers 510. The pressurized reactionchambers orcavities 510 can include or be defined, at least in part, by theinteriorsurface 505 of the base block that defines or contains the reaction vessel. The reactioncavities orchambers 510, and in turn, thereaction vessels 500 in fluid communication therewith (e.g., sharing a common headspace therewith) can be pressurized to theoperating pressures values discussed below. Further details regarding thereactor block520, including preferred sealing configurations, and rupture protection configurations,are described in the aforementioned related, co-pending, co-owned patent applicationsU.S. Ser. No. 09/177,179, U.S. Ser. No. 09/211,982, U.S. Ser. No. 09/548,848, and inPCT patent application WO 00/09255, each of which are hereby specificallyincorporated by reference.

In a particularly preferred embodiment, with further reference to Figures 4Athrough 4D, thereaction vessel 500 can further comprise at least 3feed ports 515 influid communication with thereaction chamber 510, and at least 3independent feedlines 300 providing fluid communication between the at least threefeed ports 515 andat least three corresponding, dedicated or non-dedicated reagent source vessels (e.g,through pumps, and other components of a distribution system, as described). Each ofthe three or more feed lines has adistal end 305 in fluid communication with thereaction chamber of the reaction vessel. Thedistal end 305 of thefeed lines 300 canterminate, for example, at one or more of the following positions: at the at least threefeed ports 515; at a position internal to the reaction cavity 510 (whether above or belowthe reaction vessel 500 (e.g. especially where the reaction vessel is aremovablereaction vessel 500 that shares a common headspace with thereaction cavity 510pressure boundary); or at a position internal to thereaction vessel 500. The distal end ofthe three or more feed lines can, in one embodiment, define an opening(e.g., circularopening) through which the reactant fluid can pass to enter the reaction zone of thereaction vessel. The feed lines and/or reaction vessel configuration is preferablydesigned to minimize dead volume within the reaction vessel.

In the preferred embodiment, in which the reaction vessels are provided in areactor block comprising a base block and a header block with reaction cavities formedin the base block and/or the header block, the reactor block can further comprise one ormore header gaskets situated between the header block and the base block. The headergasket(s) can serve as seals (as discussed above), and can additionally or alternativelyalso be adapted to mask the portion(s) of the header block that are exposed to thereaction cavity (cavities). Specifically, a header gasket can be a unitary, disposableheader gasket having two or more, preferably four or more masking regions that correspond (in number, and in shape) to the reaction cavities (i.e., to the exposedportions of the header block within the reaction cavities).

The reaction vessels can be a semi-continuous (i.e., semi-batch) reaction vesselshaving the multiple feed lines, but without a continuous discharge line. The semi-continuousvessels can have a discharge line for intermittent sampling, however. Ifdesired(e.g., for a continuous flow embodiment), thereaction vessel 500 can likewisebe a continuous reaction vessel, and can comprise at least one discharge line having adistal end in fluid communication with the reaction chamber of the reaction vessel. Ineither case, the feed distribution system can be a multiplexed system comprising theselection valves dedicated to each feed channel, as described above.

Each of the reaction vessels can preferably comprise one or more gas ports 522(Fig. 4B) providing fluid communication to the reaction cavity 510 (and inherently tothe reaction vessels 500) and serving, for example, as gaseous feed ports, pressure-monitoringports, pressure control ports, or gaseous purge ports. Preferably each of thereaction vessels comprises a pair ofgas ports 522. Independent pressure control foreach of the n reaction vessels is particularly important in connection with thesemicontinuous and continuous parallel reactor embodiments disclosed herein.Dedicated independent pressure control systems can maintain a constant systempressure during addition of additional feed volumes (gas or liquid), during discharge ofa portion of the reaction mixture, to account for changes in pressure effected by thereaction itself(e.g., the formation of gas-phase products during the course of thereactions), and/or to account for differences in temperature between different reactionvessels. Pressure control is preferably under the control of a microprocessor, with setpointsestablished based on the reactions and reaction conditions of interest. As shownin Figure 4B, each of thereaction vessels 500 can also include a pressure relief system,shown generally at 531. Briefly, the pressure relief system can include a reliefpassageway 531a, a rupture disk 531b(e.g., commercially available from Parr), and anexpansion volume 531c, which can for example, be an outlet flow path leading to wastecollection.

The geometry of the reaction vessel or the reaction cavity or chamber is not, byitself, particularly critical. The reaction vessels can be open or closed, but if open, arepreferably contained within a closed reaction chamber or reaction cavity that can bepressurized, substantially as described herein and in the aforementioned related patent applications. The reaction vessels can generally be substantially of the same (e.g.cylindrical) volume as compared between reaction vessels, or can be of differentvolume. Each of the reaction vessels can have a substantially uniform (e.g., circular oroval) cross section (as taken radially). In some embodiments, however, the reactionvessel can have a varying, non-uniform cross section, combining for example both anoval cross section (as taken radially) in a first (e.g., upper) portion of the reaction vesseland a circular cross section (as taken radially) in a second (e.g., lower) portion. Withreference to Figure 5A, for example, having an oval cross section (or equivalentthereof) in anupper portion 511 of thereaction cavity 510 /reaction vessel 500 canadvantageously allow for additional space on at least one side, and preferably on bothsides of a shaft-driven stirring mechanism, through which multiple feed lines can beprovided. In particular, in a preferred or particularly preferred embodiment, each of thetwo or more, preferably four or more, reaction vessels are defined by or contained in alower portion of a reaction cavity having a first size and/or shape (e.g., circular shape).The upper portion of the reaction cavity can have a second size (e.g, with a larger crosssection) and/or shape (e.g. oval shape) taken radially, relative to the size and/or shapeof the lower section, such that there is additional space for passing the feed linesthrough the upper section to the lower section of the reaction cavity.

In one preferred embodiment, the reaction vessel can be a substantially right-cylindricalvolume and can have an aspect ratio (L/D) of at least about 1.0, preferablyabout 1.5, and more preferably at least about 2, and in some embodiments at least about2.5 or at least about 3.0.

The reaction vessel preferably has a volume ranging from about 1 ml to about 1liter (l), preferably from about 1 ml to about 500 ml, and more preferably from about 1ml to about 100 ml, still more preferably from about 2 ml to about 50 ml, yet morepreferably from about 2 ml to about 25 ml, and most preferably from about 5 ml toabout 15 ml. The smaller size of the reactor allows for a decrease in the waste streamper reaction conducted. However, such a small scale still allows for generation ofenough material (e.g., in a polymerization experiment, for example, resulting in about1-5 grams of dry polymer) to do a variety of scientifically meaningful rapid and/orconventional characterizations techniques. Small-volume reaction vessels also have alarger surface-to-volume ratio (S/V) than conventionally-sized "bench-scale" vessels,and as such, can efficiently and effectively explore investigations of parameter spaces involving heat transfer or other properties for which the S/V ratio is important. Thevolume of each of the two or more, preferably four or more reaction vessels ispreferably the same between different reaction cavities, but can alternatively, varybetween cavities to investigate the effect of reaction vessel volume. In someapplications, each of the various embodiments of the invention can be advantageouslyapplied with reaction vessels having larger reaction volumes, including for example,reaction volumes of up to about 2 liters, up to about 4 liters and/or 10 liters, or more. .

Each of the reaction vessels can be pressurizable to and/or operated at pressuresrequired for the chemistry of interest. In preferred embodiments, the reaction pressuresor design pressure for the reactor can be at atmospheric pressure, or at pressures greaterthan atmospheric pressure, preferably at least about 15 psig, more preferably at least 50psig, 100 psig, yet more preferably at least about 200 psig, still more preferably at leastabout 400 psig, and in some embodiments, at least about 500 psig, at least about 700psig, or at least about 1000 psig, and in some instances, at least about 1200 psig.Preferred pressure ranges include from about atmoshperic pressure to about 3000 psig,preferably from about 100 psig to about 2500 psig, more preferably from about 200psig to about 2000 psig, and yet more preferably from about 400 psig to about 1500psig. In some embodiments, the pressures can range from about 500 psig to about 1200psig, from about 500 psig to about 1500 psig, or from about 1000 psig to about 1500psig. Such pressures and pressure ranges can be particularly applied in connection withnon-biological polymer research applications. In some applications, the reactor ispreferably hermetically sealed.

Temperature control of the reaction vessels can be effected substantially asdescribed in the aforementioned related, co-pending, co-owned patent applications U.S.Ser. No. 09/177,179, U.S. Ser. No. 09/211,982, U.S. Ser. No. 09/548,848, and in PCTpatent application WO 00/09255, each of which are hereby specifically incorporated byreference. In general, temperature control can be individual with respect to eachreaction vessel, or modular with respect to two or more, preferably four or morereaction vessels. In preferred embodiments, a reactor block can comprise or be inthermal communication with one or more temperature control elements(e.g., resistiveheaters, thermoelectric heaters, fluid-based heat exchangers,etc.) for individual ormodular temperature control. Operating temperatures can typically range from about25 C to about 300 C, preferably from about 100 C to about 200 C for many applications, and if cold-temperature applications are required, preferably from about - 100 C to about 300 C.

Stirrers

The reaction vessels are preferably mechanically stirred, and in particular, arepreferably stirred with a shaft-driven stirrer (e.g., shaft-driven impeller) stirringmechanism. The shaft-driven stirrer (e.g., impeller) can be advantageous over othertypes of stirring approaches, such as magnetic bar stirrers, mixing balls w/rockers,shaking,etc., due to higher stirring power and to the controllable variability in mixingprofile achievable through a combination of varying stirrer geometry and impellerspeed for each of the parallel reactors. The shaft-driven stirrer (e.g., impeller) can bedriven directly from a motor, or indirectly via magnetic coupling. Preferred shaft-drivenstirring embodiments are disclosed in the aforementioned related patentapplications, including, for example, U.S. Ser. No. 09/548,848 filed April 13, 2000 byTurneret al, entitled "Parallel Reactor with Internal Sensing and Method of UsingSame". The particular geometry of the shaft-driven stirrer(e.g., impeller) is notnarrowly critical, and can vary depending on the type of mixing desired for a particularreaction of interest. For many reactions, it is desirable to employ a shaft-driven stirrer(e.g., impeller) having a geometry that provides for substantial axial and substantialradial mixing (the axial direction being considered to be substantially parallel to theaxis of the shaft of the impeller). A number of generally preferred, exemplary shaft-drivenstirrer (e.g., impeller) geometries are shown in Figures 3A through 3F. Withrespect to the auger-type shaft-driven stirrer(e.g., impeller) depicted in Figure 3C, thenumber of turns per inch, and the pitch can be adjusted as desired to achieve a desiredmixing profile. Moreover, the pitch can be fixed or variable, and can be controllablyvaried throughout the course of the reaction. In operation, it may be desirable tochange impeller speed (and where possible, other variables) to account for changes influid viscosity within the reaction vessels during the course of the reactions. It may alsobe desirable to have different impeller geometries in the stirrers for each of two or moredifferent reaction vessels, such that differences in mixing profiles can be investigated inparallel reactions.

With further reference to the figures, thereaction vessels 500 in these preferredand particularly preferred embodiments can further comprise a shaft-driven impeller stirrer (850, Figs. 2A through 2D and 3A through 3E, not shown in Figs. 4A through4D), and preferably having a magnetically-coupleddrive motor 800. Thedrive motor800 can alternatively be directly coupled to the shaft /impeller 850. The shaft-drivenstirrer 850 can be mounted on, and comprised in theheader block 540 of thereactorblock 520, as shown in Figures 4A through 4D, and in Figure 4H, with theheader block520 /stirrer 850 subassembly positioned over thebase block 530 to provide a sealed,pressurizable, reaction chamber 510 (once mounted and positioned). A cover 550 (Fig.4H) can cover the two ormore drive motors 800, in a sealing or non-sealing manner, asappropriate for the operating environment.

The shaft-drivenimpeller stirrer 850 can be a unitary shaft that is directlycoupled to thedrive motor 800. Alternatively, with reference to Figures 3F through 3I,the shaft-driven stirrer can be a two-piece shaft comprising a firstupper shaft 851engageable with thedrive motor 800 and a secondlower shaft 852 having the stirringelement 854. The firstupper shaft 851 and the secondlower shaft 852 can bedetachably connected from each other (e.g., for cleaning and/or disposal / replacement)through a latching mechanism, generally referred to in Figures 3G and 3H as 856. Alatching mechanism 856 comprises alatch spring 857 secured to the firstupper shaft851, that can releasably engage acircumferential indent 858 near the upper end 859(Fig. 3F) of the secondlower shaft 852. With reference to Figure 3I, an alternative,spring-less latching mechanism 856 can be a pressure-fitted connection, in which theupper portion of a second lower shaft 852 (e.g., such as that shown in Fig. 3F - notshown in Fig. 31) can be pressure-fitted into a slottedaperture 855 of a firstupper shaft851. In either of the aforementioned embodiments, a drive mechanism, such as acombination of adrive key 860 on the secondlower shaft 852 and alock 862 on thefirst upper shaft 861 (or vice versa) can be employed with thelatch mechanism 856.Advantageously, the secondlower shaft 852 of the two-piece shaft 850 can bedisposable, as indicated above.

As an alternative to, or in addition to a disposable shaft (e.g., a disposablesecond lower shaft 852), the stirring system can, for each shaft-driven impeller, alsocomprise one or more shaft covers adapted to mask at least a non-disposable portion ofthe shaft-driven impeller. Specifically, with reference to Figures 3A through 3I, a shaftcover (not shown) can mask the entire shaft 850 (including the impeller portion), or aportion thereof- such as masking a first, non-disposableupper shaft 851 of a two-piece shaft 850, where the secondlower shaft 852 is a disposable shaft. Use of suchdisposable shaft covers facilitates clean-up after the reaction of interest.

Feed Lines - General

The number of independent feed lines (e.g., liquid reagent feed lines) in eachreaction vessel can be at least two feed lines, but for these preferred and particularlypreferred embodiments is preferably at least 3, more preferably at least 4, morepreferably at least 8, and in other embodiments, can be integer numbers up to about 10or more(e.g, at least 12 or at least 16), or in some cases up to about 20, and in general,can range from about 4 to about N (as defined above) and preferably from about 4 toabout 20 or from about 4 to about 10.

The feed lines 300 and discharge line(s) 600 can be of any suitable size, butpreferably have an inside diameter(e.g., orifice size) ranging from about 10 µm toabout 1 mm, preferably from about 50 µm to about 500 µm, and most preferably fromabout 100 µm to about 250 µm. Smaller orifice size, especially when applied incombination controllable valve switching, and finely-controlled pumps, is particularlyadvantageous over prior art systems due to the fine volume control achievable whenadding additional reagents during the course of the several reactions. In particular, theat least two, preferably at least three, more preferably at least four feed lines have aninside diameter of not more than about 1 mm. In some embodiments, the outsidediameter is not more than about 1 mm, and the inside diameter is not more than about700 µm.

The feed lines may be made of any material or combination of materials.Portions of the feed lines in contact with the reaction environment should preferably becompatible with the chemistry of interest. The feed lines can generally be of anyspatially suitable geometry(e.g., circular, square, rectangular,etc. in cross-sectionalshape). In general, feed lines may be provided as capillaries, channels (e.g.,micromachined channels - typically having a diameter of less than about 1 mm, andpreferably of less than about 100 µm), tubing,etc.. The feed lines can be rigid feedlines, or non-rigid feed lines under reaction-pressure conditions. The feed line materialmay include, for example, glass (e.g., fused silica), polymers (e.g., PTFE (Teflon),polyethylene, PEEK) or metals or alloys (e.g., stainless steel) - or any other materialsuitable for the chemistry (for the portion in contact with the reaction environment), suitable for the pressure and flow conditions of the reaction system, and if necessary,suitable for use with various connectors,etc. Although shown in the various figures asbeing capillaries and/or flexible tubing, it is likewise envisioned that other suitableconduits, such as micromachined channels could be employed as part of the feed and/ordischarge distribution system.

In some embodiments, at least a portion of the feed lines can be integral with(e.g., machined (including micromachined) into) the reactor block (e.g. into the headerblock and/or the base block). Various other components of the feed-distributionsystem(e.g. valving) and/or of a sampling system could likewise be integral with thereactor block. Some specific embodiments of integral feed distribution are disclosed inrelated, co-owned U.S. patent application Ser. No. 09/826,606 entitled "ParallelReactor for Sampling and Conducting In-Situ Flow Through Reactions and a Methodof Using Same", filed April 5,2001 by Chandleret al., which is hereby incorporated byreference in its entirety for all purposes.

Varying Feed Line Size

In some embodiments, the reaction vessels comprise at least two, at least threefeed lines, or preferably at least four feed lines, and one or more of the at least threefeed lines (or at least four feed lines), or a first subset thereof, have a different insidediameter (e.g., orifice size) or cross-sectional area relative to the one or more other ofthe at least three feed lines, or a second subset thereof. Variable diameter or cross-sectionalarea of the feed / discharge lines offers a further control variable for activelycontrolling the overall volume and rate of feed addition to each of the reaction vessels.It is also typically desirable to have small-diameter tubing as the feed line into eachreaction vessel, so that small drops are delivered more "evenly" (i.e., temporally morecontinuous) to the reaction, and so that the reagent being added has a short contact timewith heated surfaces before being introduced into the reaction mixture. Thecombination of smaller and larger sizes is also indicated in connection with this aspectof the invention. Since small-diameter tubing limits flow rates, it may be desirable tohave larger diameter tubing for reagents delivered in larger volume (such as solvent) orat faster feed rates, and smaller diameter tubing for reagents delivered in smallervolume (such as catalysts and initiators) or at slower feed rates. As a non-limitingexample, the inside diameter for one or more of the feed lines can be less than about 500 µm while another of the feed lines going to the same reaction vessel can be about500 µm or more.

Feed-Line Grouping /Modular Feed-Line Subassemblies (e.g., Ferrules)

The feed lines can be grouped for service to each of the two or more, preferablyfour or more reaction vessels. With reference to Figure 5A, for example, guidebrackets 542 can be mounted on aheader block 540 of thereactor block 520 to guide atleast three, preferably at least fourfeed lines 300 into the reactor block 520 - enteringeither through the header block 540 (as shown) or alternatively through the base block530 (not shown).

Moreover, the at least two, at least three, or preferably at least four feed linescan enter the reactor block individually, as shown for example in Figures 4A through4F, and in Figure 5A, and can be sealed using epoxies or other sealants (not shown), orusing individually mounted mechanical fittings (e.g., individual swage-lock typefittings, not shown) mounted in thefeed ports 515 of thereactor block 520.Alternatively, and advantageously, the at least three, preferably at least four feed linescan enter into the reactor block in modular fashion as a bundled collective group.Preferably, the modular group of feed lines can be removably attached - preferablyefficiently connected and/or disconnected to and/or from the reactor block through amodular feed-line subassembly. Specifically, the at least three, preferably at least fourfeed lines can be provided to the reactor block (and ultimately to one or more reactionvessels) through one or more modular feed-line subassemblies. In some embodiments,higher numbers of feed lines can be accommodated through each of the feed-linesubassemblies - including for example at least six feed lines, preferably at least eightfeed lines, at least twelve feed lines, at least sixteen feed lines or at least twenty-fourlines. Each of the feed-line subassemblies is adapted to releasable engage the reactorblock and to support at least two, preferably at least three, more preferably at least fourfeed lines passing into the reaction cavity or reaction vessel.

The particular design of the feed-line subassemlies is not narrowly critical. Inone exemplary embodiment, a feed-line entrance bracket having at least two, preferablyat least three, more preferably at least four individual mechanical fittings (e.g. swage-locktype fittings) mounted on a common bracket can be employed as the feed-linesubsassembly. In a preferred embodiment, with reference to Figure 4H and Figures 5B through 5H, the modular feed-line subassembly can be a ferrule 560 (referenced asshown without a fastener in Figures 5D through 5H by reference numeral 560'). Theferrule 560 (560') comprises two ormore apertures 562 adapted to support, andpreferably to sealingly support the at least twofeed lines 300 when theferrule 560 isengaged with the reactor block 520 (e.g., with header block 540). Regardless of theparticular configuration for the modular feed-line subassembly, the subassembly ispreferably engaged either with the header block 540 (as shown) or alternatively withthebase block 530 of thereactor block 520. In a preferred embodiment, theheaderblock 540 or thebase block 530 can comprise four or more feed-linesubassemblyreceiving ports 570. Each of the receivingports 570 is in fluid communication with thereaction cavity 510 (and with the reaction vessel 500) and is adapted to receive one oftheferrules 560, and preferably to releasably and to sealingly engage one of theferrules560. With reference to Figures 5E through 5H, each of the one or more ferrules 560'comprises a firstinterior end 561 for insertion into the corresponding receivingport570 in thereactor block 520, a secondexterior end 563 substantially opposing the firstinterior end 561, two or more, preferably four or moreinternal apertures 562 extendingfrom the firstinterior end 561 to the secondexterior end 563 for supporting the at leastfourliquid feed lines 300 passing into one of thereaction vessels 500. The ferrules560' further comprise anexternal side surface 564 including a taperedportion 565, thetaperedportion 565 having a smaller cross-section at positions closer to the firstinteriorend 561 relative to positions farther from the firstinterior end 561, the taperedportion565 being configured to correspond to atapered surface 572 defining a portion of thereceivingport 570. The ferrule 560' also comprises afastener 568 for releasablyengaging at least thetapered portion 565 of the ferrule 560 (560') with thecorresponding taperedsurface 572 of the receivingport 570. Thefastener 568 can be,for example, a hollow threaded nut that engages corresponding threads on the receivingport 570. The ferrule 560' can be of a compressible material such that when engaged,the taperedportion 565 of the ferrule 560' seals with the corresponding taperedsurface572 of the receivingport 570, and each of the at least twoapertures 562 seals thecorresponding at least twofeed lines 300. In any case, as shown in Figure 5D,preferably two or more modular feed-line subassemblies 560 can providefeed lines 300to thesame reaction cavity 510 /reaction vessel 500. The two or more feed-line subassemblies 560 can be orientated on the same side or different (e.g., opposing) sidesof the reactor block(e.g., header block).

Additionally, regardless of the particular design, the feed-line subassemblies(e.g. ferrules) can further comprise one or more apertures adapted to support, andpreferably sealing support one or more instrumentation lines, including for example,lines for thermocouples, pressure-sensors, pH sensors,in-situ analysis(e.g., fiber-opticprobes),etc.

Distal-End Position

In the preferred or particularly preferred embodiment (and in otherembodiments having at least two, preferably at least three, more preferably at least fourfeed lines 300 for a reaction vessel or for each of two or more, preferably four or morereaction vessels 500) thedistal end 305 of each of thefeed lines 300 can be positionedto substantially the same depth in thereaction cavity 510 or reaction vessel 500 (asshown in Fig. 4B). Alternatively, although not shown in the figures, thedistal end 305of one or more of thefeed lines 300 preferably some first subset of the total number offeed lines 300, can be positioned lower in thereaction cavity 510 orreaction vessel 500as compared to the distal end of one or more other feed lines, preferably some othersecond subset of the total number of feed lines. In particular, if a liquid-phase reactionis being run with a gaseous headspace, thedistal end 305 of thefeed lines 300 can bepositioned to terminate in the gas phase (shorter extension into reaction chamber 510 )or in the liquid phase (longer extension into the reaction chamber 510). It may beparticularly advantageous for some such applications to have at least some of the feedlines terminating in the gas phase, and at least some of the feed lines terminating in theliquid phase (i.e., directly into the liquid reaction mixture). Without being bound bytheory not specifically recited in the claims, differences in the surface tensionassociated with the interface defined between thedistal end 305 of thefeed lines 300and the gas phase (the gas interface) as compared to the surface tension associated withthe interface defined between thedistal end 305 of thefeed lines 300 and the liquidphase (the liquid interface), can result in differences in feed delivery, and provide agreater degree and/or different nature of feed control. That is, feeding through the gasinterface can result in temporally intermittent feeding profile due to the formation ofdrops at thedistal end 305 of thefeed lines 300, whereas feeding through the liquid interface can result in a substantially temporally continuous feeding profile (assumingsubstantial phase compatibility between liquid feed and the liquid reaction mixture). Inany case, the at least two, preferably at least three, and more preferably at least fourfeed lines can be supported in thereaction cavity 310 by one or more guide posts 544(Fig. 5D). The guide post 544 can be supported by thehead block 540 through guide-postbolt 546.

Detachable, Multi-Section Feed Lines /Parallel Feed-Line Interface

In the preferred and particularly preferred embodiments and in otherembodiments having at least two, preferably at least three, more preferably at least fourfeed lines 300 for a reaction vessel or for each of two or more, preferably four or morereaction vessels 500), thefeed lines 300 can comprise at least a first section and asecond section in fluid communication with each other. Advantageously, the secondsection can be detachably connected from / releasably engaged with the first section ata feed-line junction, thereby allowing a second section contaminated from the reaction,for example (i.e., having a distal end in the reaction mixture or in the reaction vessel inproximity to the reaction mixture), to be detached, cleaned or disposed, and replacedwith the cleaned or new second section.

The first and second sections of the feed line can be detachably connected(releasably engaged) from each other by an suitable approach, including for exampleindividual mechanical connectors (e.g., union couplers), or thermal heat-shrinking. In apreferred approach, with reference to Figures 4H and 6A, a parallel feed-line interface580 can provide for fluid communication between afirst section 300a and asecondsection 300b of each of at least four liquid feed lines 300. The feed-line interface 580can comprise a modular first source-side piece 581 and a modular second reactor-sidepiece 582 that are releasably engagable (e.g., through a bolted connection) with eachother to provide the fluid communication between the first andsecond sections 300a,300b of thefeed line 300. Additionally or alternatively, theinterface 580 can bereleasably connected to thefirst section 300a (e.g., through heat shrink of thefirstsection 300a ontoannular nodules 584 of the first source-side piece 581, as shown inFigure 6A) and additionally or alternatively, to thesecond section 300b (e.g., throughmechanical connectors 586, of each of the at least four liquid feed lines). As shown,theinterface 580, 580' can be mounted on or otherwise supported by the reactor block, but could alternatively (or additionally foradditional interfaces 580, 580') be separatefrom the reactor block (e.g., used for multiple connections elsewhere in the feeddistribution system, such as by the one or more distribution valves 400).

The junction point between the first andsecond sections 300a, 300b offeedlines 300 can be external to the reaction cavity (e.g. as shown in Fig. 6A, withparallelinerface 580 connection), or can be internal to the reaction cavity (e.g. as shown in Fig.5D, with individual heat-shrink connection). More particularly in one embodiment, thefirst section 300a is positioned entirely outside of thereaction cavity 510, or at leastpartially outside of thereaction cavity 510, preferably at least outside of the reactionvessel 500 - such that it is substantially uncontaminated by the liquid reaction mixture(i.e., can be used again, preferably without or with only nominal cleaning effort).Hence, at least a portion of thefirst section 300a can be inside thereaction cavity 510.

Thefeed line 300 can additionally comprise athird section 300c or highernumbers of sections, each in fluid communication with each other, and detachablyconnected as described above, individually or in modular fashion - for example withtheinterface 580. Moreover, different types of feed line materials can be employedwith respect to each section, depending on the desired attributes for that section of thefeed line. In a preferred exemplary, non-limiting approach, the feed line can include afirst section 300a of polymer-coated (e.g. polyimide-coated) fused silica detachablyconnected (e.g., by heat-shrink) to asecond section 300b of PEEK or Teflon,substantially as shown in Figure 5D. Thefirst section 300a can, in turn, be detachablyconnected to athird section 300c of thefeed line 300, thethird section 300c beingTeflon or PEEK. In another exemplary, non-limiting embodiment, a Teflon or PEEKtubingfirst section 300a can be detachably connected to a stainless steel tubingsecondsection 300b (e.g., by mechanical connection), as shown in Figure 6A.

Multiple Modules

The reaction vessels can be independent of each other, or can be combined in asingle module, as disclosed in Figures 4A through 4H, Figures 5A through 5C andFigure 6A. Banks of modules can be combined to form a parallel reaction vessel havelarge numbers of reaction vessels.

The entire reactor system may be placed in an inert atmosphere or controlledatmosphere chamber (such as a glovebox).

Use /Operation

The reactor is useful for polymerization reactions as well as for a broader rangeof organic or inorganic reaction processes where it is desirable to have feed additionsduring the course of the reaction - for example, to control exothermicity, to maintainrelatively small, steady-state concentrations of reactants, or to effect different stagedphases of a multistep reaction. The apparatus also has applications involving chemicalprocesses that do not necessarily involve a chemical reaction - such formulations,blending, or crystallization processes. Although preferably designed for high-pressureapplications, the apparatus and features disclosed herein can also be used at relative lowpressures, including atmospheric pressure. In lower pressure applications, theapparatus is preferably (but not necessarily) at least hermetically sealed.

Many reactions (or interactions that do not necessarily involve the makingand/or breaking of chemical bonds, such as blending, formulations, crystallization)require the slow addition of one or more components to a reaction over time. Thepresently-described reactor can be equipped with the appropriate tubing and valving toadd a defined amount of a reactant chemical to any selected reactor well, over a definedperiod of time (within the constraints of the reactor volume, pump precision and themaximum flow rate controlled by pump speed, tube diameter and chemical viscosity).Multiple components are often important as there may be several stages to a reactionwhich each may require several different chemicals to be added (initiators, monomers,boosters, quenching reagents, etc.). The added reagents may generally be gas and/orliquid, depending on the reaction of interest Such multi-feed protocols are particularlyadvantageous with polymerization reactions such as emulsion polymerizations. In thisarea, for example, it is desirable to add several monomers, water, surfactant solution,initiators, and redox reagents all in a concerted, time-controlled manner, in multiplestages during the course of a reaction.

The extent, order and temporal profile (e.g., rate) of feed additions can becarefully controlled using the present invention, as can the rate and/or order ofdischarges. In particular, the control system can include control of the pumps, controlof the switching valves, pressure controllers, all integrated. In general, the control isflexible, and advantageously, it can be coordinated with library design software (e.g.,"Library Studio™", Symyx Technologies, Inc., Santa Clara, CA) and/or synthesis control software (e.g., "Impressionist™", Symyx Technologies, Inc., Santa Clara, CA),such as is disclosed in the aforementioned related patent applications. Oneadvantageous application of the described system is that sensitive reagents may bemanipulated in pumps in lines on a benchtop or in a simple hood, so that blanketing theentire reactor system in inert atmosphere may not be necessary, even for sensitivechemistry. In fact, one or more distribution channels may be used for gas distribution,either to flush the reactors with inert atmosphere before beginning a reaction, or forintroduction of metered amounts of gaseous reagents.

Reaction protocols that can be advantageously effected with the parallel reactorof the invention can generally be categorized into three temporal phases - initialreaction charge ("IRC") as a 1^st phase, slow additions of one or more reagents ("slowadds") as a second phase, and finish or mop-up ("finish") as a third phase.

In the initial reaction charge phase, the system is sealed, and typically purgedwith inert gas. Some set of starting reagents may be added to the reaction vessels viaexternal means prior to closure and purging, or using the distribution arid feed systemdescribed either prior to or after closure and purging. The reaction vessels are thenheated to the desired (initial) temperatures (each cell may have a different temperature)while at the same time stirring each initial mixture with an shaft-driven stirring paddle.Typically, feed control is less significant, albeit still important, in the initial chargestage.

In the second, slow-add phase, a number of reagents(e.g. eight reagents) are fedto the reaction vessels, preferably independently of each other, using the distributionand feed system described. Exemplary slow additions for polymerizations includemonomer additions, initiator trickle, surfactant trickle, make-up solvent,etc.Significantly, the system has the capabilities to control the total volume of each of thereagents being fed to each reactor, the sequence (relative order) of each feed addition,and temporal profile(e.g., feed rate, temporally incrementalvs. temporally continuous,number of increments, size of increments(e.g., volume or time of increments),etc.) ofeach feed addition. Feed control is particularly important in connection with thissecond, slow-add phase. The particular nature and/or degree of feed control capabilitieswill depend on the arrangement of the feed distribution system. For example, in reactorsystems having eight dedicated feed lines feeding eight reagents to each of eightreaction vessels (e.g., through a distribution system that includes feeding each of the eight reagents from its source vessels through its dedicated pump and its dedicated feeddistribution valve), addition volumes can be carefully and efficiently controlled - sinceeach feed path is dedicated between one reagent and one of the eight reactors. Incontrast, in reactor systems having some non-dedicated feed paths (e.g. by feedingeight reagents through three dedicated feed lines and two non-dedicated feed lines toeach of eight reaction vessels), addition volumes for the non-dedicated (i.e., shared)feed lines may be less carefully (e.g., some mixing of reagents allowed, volume of thefeed tubes and/or uniformity of feed tubes affect the dispensed volume) and/or lessefficiently (e.g., some intermittent rinsing steps required) controlled. Hence, dedicatedsystems as described connection with Figure 2G are preferred with respect toefficiency and control. Other feed control aspects described above can also beincorporated into a particular system. Generally, it is most advantageous (in terms ofdispensing precision and flexibility) for each feed distribution channel to be dedicatedto one homogeneous liquid reagent solution. However, it is also possible to dispenseheterogeneous mixtures, including mixtures of immiscible liquids and slurries of solids,within the metering precision, pump design and chemical compatibility constraintsimposed by the specific chemistry.

In the third, finish phase, reagents can be added for various purposes, such as tostop (e.g., quench) the reaction, to consume left-over reactant, or to impart usefulproperties to the resulting product mixture (e.g., stabilisers, anti-microbial agents,etc.).

Regardless of the particular phase of the reaction, several feed strategies can beeffected for feeding multiple reagents to each of the multiple reactors. The followingfeed strategies can be effectively employed for various configurations of the feeddistribution system. For example, in systems where each of eight feed lines to each ofeight reaction vessels has its own source vessel (i.e. sixty-four source vessels in total)with straight-line feeding from each of the source vessels through dedicated pumpsdirectly to the reaction vessel (without a distribution valve), complete operationalflexibility is retained with respect to feed strategy. That is, reagent 1 (R1) can besimultaneously fed to any or each of the eight reaction vessels, serially orsimultaneously with any or each of the other reagents. Substantial operationalflexibility can also be achieved - with significant simplification and savings in cost - using systems where each of the eight feed lines to each of the eight reaction vesselshas only one source vessel, but with a dedicated feed distribution system as described above in connection with Figure 2G. Regardless of the particular configuration, theparallel reactor / multi-feed system of the invention can generally be operated andcontrolled continuously and in parallel (simultaneously) with respect to each reactionvessel. However, because chemical reactions typically occur over longer periods oftime, strategies involving staggered, serial control over the reactions can be effectedwithout substantially affecting the reaction performance, for many operations ofinterest.

According to one such staggered control strategy, reactor feed control iseffected for each reaction vessel on a rotating serial basis - considering and providingthe feed requirements for the first reaction vessel, then the second reaction vessel, thenthe third reaction vessel,etc., and continuing serially until each of the reaction vesselshave been controlled during this first round of control. Control attention is then rotatedback to the first vessel, to further consider and provide the feed requirements thereto,and then sequentially through the second reaction vessel,etc. until each of the reactionvessels have been controlled during the second round of control. The sequential controlstrategy is then repeated until each of the reactions have been completed. Suchsequential control strategy can be effected from a "per reactor" (i.e., "per reaction-vessel")framework - with a single overall control system focusing control attention onall of the feed requirements for a particular reaction at that time, and controlling all ofthe feed streams to meet those requirements at that time. Alternatively, control can beeffected from a "per reagent" (or "per feed line") framework, with multipleindependent control systems. Here, each feed line is independently controlled on astaggered basis - that is, independent of the control of other feed lines, with delays orpasses (no control effected), as appropriate, to allow for required sequence order ofdifferent reagents. Regardless of the control framework, each control event associatedwith a particular reactor can include, for example, determining the feed requirementsfor that stage of the reaction - typically by reference to a pre-programed recipe of feedversus time of reaction, but optionally including some real-time or near-real-timefeedback loop, with the feed being adjusted to meet a predetermined setpoint (e.g.,feeding for pH control, or temperature control). Various feeds can then be added to thereaction vessel to satisfy the then-current feed requirements, for example, by operatingthe pumps (e.g., syringe pumps), by opening valves in a particular feed line at anappropriate time to select the appropriate receiving vessel and align it to the proper feed in the proper order, by injecting the required fraction of the total amount of that reagentto be added, and then by closing that valve and opening the next one. Rapidly cyclingthrough the valves in each line - under either framework - allows for pseudo-continuousaddition of reagents.

More specifically, chemical reactions can be effected in a parallel, semi-continuousor continuous reactor, preferably a pressure reactor pressurizable to not lessthan about 50 psig. The reactor can comprise four or more semi-continuous orcontinuous reaction vessels, four or more liquid reagent source vessels, and at least fourliquid feed lines providing selectable fluid communication between the four or moreliquid reagent source vessels and the four or more reaction vessels, as follows. Thevolume of the reaction vessels is preferably less than 1 liter. A chemical reaction isinitiated in each of the four or more reaction vessels under reaction conditions that caninclude a reaction pressure of not less than about 50 psig. The chemical reaction can besequentially initiated in each of the four or more reaction vessels, or alternatively, it canbe initiated in each of the four or more reaction vessels at substantially the same time.The four or more liquid reagents are fed into the four or more reaction vessels duringthe reaction under the reaction conditions, while controlling, for each reaction vessel, atotal volume of each of the liquid reagents being fed to the reaction vessel during thereaction, a number of stages in which the total volume for each of the liquid reagentsare fed to the reaction vessel during the reaction, a stage volume defined by apercentage of the total volume associated with each of the stages for each of the liquidreagents, and a feed sequence defined by a relative order in which the stages for each ofthe liquid reagents are fed to the reaction vessel during the reaction. The total volumecan be the same or different as compared between different reagents. The number ofstages can be the same or different as compared between different reagents, and can beone or more stages, and is preferably at least 2 stages, more preferably at least fourstages, and in some cases, more preferably at least ten, at least one hundred stages orhigher numbers. The number of stages can typically range from about 1 to about 1000,preferably from about 1 to about 100, and more preferably from about 2 to about 20.The stage volume can also be the same or different as compared between differentstages for each of the liquid reagents. The feed sequence can include, with respect to aparticular reaction vessel, sequential feeds of various different reagents, orsimultaneous (coinciding or overlapping) feeds of various different reagents to that reaction vessel. The total volume, number of stages, stage volumes and feed sequencecan be selected with consideration to the involved chemistries.

Preferably, control is also effected over a temporal profile associated with feedaddition to the reaction vessel for each of the stages for each of the liquid reagents. Thetemporal profile for each stage can be defined by a number of feed increments in whichthe stage volume is added to the reaction vessel, and the period of time in which thestage volume is added to the reaction vessel. Each feed increment represents aseparate, discrete addition of a reagent to the reaction mixture in the reaction vessel.With syringe-type pumps, for example, each feed increment can correspond to anindividual pump operation. The number of feed increments can be the same ordifferent as compared between each of the stages, and between each of the reagents,and can generally be one or more increments. A single feed increment represents atemporally continuous feed over the period of feeding the stage volume. The numberof feed increments for each stage can, in some embodiments, be at least twoincrements, at least four increments, and in some cases, at least ten increments, at leastone hundred increments or higher numbers. The number of increments can typicallyrange from about 1 to about 1000, preferably from about 1 to about 100, and morepreferably from about 2 to about 20. The duration or period over which the stagevolume is added to the reaction vessel can be, equivalently, expressed as a start time foradding each stage volume and a stop time for adding each stage volumes. Theincrement volumes (e.g., defined as a percentage of the stage volumes) can also becontrolled, and can be the same or different as compared between different incrementsof a stage. Likewise, in some embodiments, with some types of pumps, the actualdelivery flowrate can be controlled for each feed increment added to the reactionvessel.

The feed control systems can include one or more microprocessors forcontrolling the operation of the various pumps, distribution valves, etc., substantially asdescribed. The control system can also include one or more clocks or other timingdevices for controlling the feed sequence of the various stages for the various reagents,and within each stage, for controlling the incremental feed additions. A single masterclock can be used alone, and/or in conjunction with additional clocks, such asadditional subservient clocks. In one embodiment, each reaction vessel can have its'own associated clock, alone, or in conjunction with a master clock. In an supplemental or alternative embodiment, each feed line (or feed pump) can have its' own associatedclock. The control clocks can also be used in connection with controlling otherreaction parameters (pressure, temperature, etc), in addition to feed control.

In preferred embodiments, feed control is effected sequentially, on a rotatingbasis (e.g., rotating through each of the four or more reactors, or through some subsetthereof), for each of the four or more reaction vessels during the reaction. Morespecifically, such sequential control is effected by (i) considering and providing thefeed requirements for a first reaction vessel at a first time after initiation of thechemical reaction therein, and thereafter, (ii) by considering and providing the feedrequirements for a second reaction vessel at a second time after initiation of thechemical reaction therein, and thereafter, (iii) by considering and providing the feedrequirements for a third reaction vessel at a third time after initiation of the chemicalreaction therein, and thereafter, (iv) by considering and providing the feed requirementsfor a fourth reaction vessel at a fourth time after initiation of the chemical reactiontherein. Thereafter, such sequential control is continued by (v) reconsidering andproviding additional feed requirements for the first reaction vessel at a fifth time afterinitiation of the chemical reaction therein, the fifth time being a time later than the firsttime, and thereafter, (vi) by reconsidering and providing additional feed requirementsfor the second reaction vessel at a sixth time after initiation of the chemical reactiontherein, the sixth time being a time later than the second time, and thereafter, (vii) byreconsidering and providing additional feed requirements for the third reaction vessel ata seventh time after initiation of the chemical reaction therein, the seventh time being atime later than the third time, and thereafter, (iv) by reconsidering and providingadditional feed requirements for the fourth reaction vessel at a eighth time afterinitiation of the chemical reaction therein, the eighth time being a time later than thefourth time. In one operational variation, the chemical reaction can be sequentiallyinitiated in each of the four or more reaction vessels such that the time elapsed betweenreaction initiation and the first, second, third and fourth times at which the feedrequirements are considered and provided for the first, second, third and fourth reactionvessels, respectively, are substantially the same as compared between reaction vessels.

Several different triggering events can be employed in such staggered controlstrategies for advancing the sequence of control from one reaction vessel to the next inthe series. For example, the advance of control can be based solely on regular, recurring time intervals - where control attention is paid to each reaction vessel in turnfor a set period of time (e.g., two minutes), with the feed requirements updated to theextent possible during that set period of time, and then advanced to the next reactionvessel. In an alternative approach, the advance of control can be task-oriented, ratherthan being based solely on preestablished time intervals. In such a task-orientedapproach, advance of control occurs only after the feed requirements for the controlledreaction have been completely updated for the reaction occurring therein. That is,control attention is paid to a first reaction vessel and the feed requirements for thatreaction vessel are adjusted until fully updated (i.e., the actual feed inputs are matchedwith the preset feed requirements, for that moment in time). Thereafter, control canadvance to the next reaction vessels, and so on in serial staggered fashion. The task-orientedapproach for advancing control offers substantial advantage over a stricttemporal approach, since it gives the user greater flexibility in pre-programming thecontrol scheme or control plan for the reactions. In short, the time required to effect aparticular feed change is not arbitrarily limited by the requirement to advance control tothe next reaction vessel.

In a preferred approach, feed control is effected under software or firmwarecontrol, with a graphical user interface (GUI) for a reactor operator to input feedrequirements and/or track the reaction progress in each reactor. According to apreferred approach, the software is programmed to effect a staggered feed control, froma reactor framework, with the control event being triggered on a task-oriented basis,based on predefined user input feed requirements, on real-time or near-real-time feedback control, or combinations thereof.

Preferably, a user can define a detailed feed plan (feed recipe) for the course ofreaction associated with each of the two or more, preferably four or more reactionvessels. As noted, such feed recipes can generally include specification of the totalvolume of each of the reagents being fed to each reactor, the number of stages, thestage volume, the sequence (relative order) of each feed addition (e.g., of each of thestages), and temporal feed profile (e.g., feed rate, temporally incrementalvs. temporallycontinuous, number of feed increments, size of feed increments,etc.) for each feedaddition(e.g., for each of the stages) . In one approach, particularly suited to a feeddistribution configuration similar to that described in connection with Figure 2G, anexperimental set-up can be established as follows. With reference to Figure 7, the broad experimental parameters, total number of dedicated feed channels, the total number ofreaction vessels, and the total number of feed stages are specified(e.g., an experimentusing two feeds to each of four vessels, with feed delivery in five stages). (Step A, Fig.7A). Then, the planned total volume for each feed for each vessel is mapped out(e.g.in a grid). (Step B, Fig. 7A). These preceding steps can be performed using, forexample, Library Studio™ (Symyx Technologies, Santa Clara, CA). For each stage, astage volume, a stage starting time, a stage ending time (collectively defining a feedperiod for that stage) and maximum number of feed partitions or feed increments isdefined by the user. (Step C, Fig. 7A). The maximum number of feed partitions or feedincrements determines the minimum volume per dispensing event for that stage. Each"mapping" of one reagent to one vessel may be dispensed as one single dispense at anygiven time, or may be broken into two or more dispenses over any arbitrary length oftime. Typically, as noted above, to achieve "pseudo semi-continuous" feeding, amapping will be divided into about 10 to 1000 dispenses, depending on the dispensingprecision of the pump system, and the "smoothness" of addition required by thechemical system. Multiple mappings can, in some embodiments, be dispensedsimultaneously. Also, it may be desirable to design the overall final composition of anexperiment or library, and then conduct multiple experiments with a given compositiondiffering only in the timing, "smoothness" of addition, temperature control over time,stirring rate, and order of addition of reagents. In any case, the defined stage timingand feed partition increments are overlaid (i.e., applied) onto the mapped plan volume,to define the detailed feed plan (feed recipe). (Step D, Figure 7A).

The system can then be operated to implement the recipe during the course ofthe reaction, in a staggered feed control, with a reactor framework (controlling feedadditions to each reactor at a time), and with the control event being triggered on atask-oriented basis (finishing one task before sequencing to the next reaction vessel.The data from the recipe file is loaded into the control software, and a check is done forerrors in recipe plan values. A data structure is then created in software to implementthe loaded recipe plan data, and to thereby run the experiment. Once the reaction clockis started (can be user defined or effected), the software sequences through each vesselin series, and determines whether a feed requirement exists for that reaction vesselbased on the current time and the associated recipe plan for that feed for that vessel forthat time. If a feed requirement exists, that feed is dispense into the reaction vessel. Like determinations and if necessary, dispensing (feeding) events are effected for eachof the feeds for that vessel for that time. Once the feed requirements have been updatedfor that reaction vessel, the software sequences to the next reaction vessel included inthe experimental setup, and proceeds in a similar manner. Such operations continueuntil the experiment is complete. Once the experiment has been completed, thesoftware writes a log-file and/or report to document the actual feeding during theexperiment.

The following examples illustrate the principles and advantages of theinvention.

Example 1

A parallel semi-batch reactor having eight reaction vessels was configured asfollows: an array of eight sealed stainless steel reactor chambers, each equipped withspeed-controlled rotary shaft stirrer paddles, disposable glass liner reaction vessels withvolume capacity of about 12 ml, argon gas manifold inlet and outlet, thermostaticallycontrolled heating, and five inlet lines into each of the eight reactor vessels, supplied byfive pump and valve distribution systems of the invention. The feed lines of eachdistribution system were primed with the corresponding five liquid reagent solutionsdescribed below. The reactor was assembled in a clean, empty state, and sealed. Thereactor was pressurized 5 times with argon to a pressure of 60 psig, followed by ventingto flush air from the system, and then was maintained under an ambient (1 atm) argonatmosphere during the course of the reaction.

FeedNumber	Label	Composition
1	Monomer mix	butyl acrylate, 86.5% methyl methacrylate, 9.5% acrylic acid, 3.0% hydroxypropyl acrylate, 1.0%
2	Styrene	styrene, 100%
3	Water	water, 100%
4	Surfactant	Rhodacal A246L (Na alpha olefin sulfonate) 10.0% water, 90.0%
5	Initiator	potassium persulfate, 4.0% water, 96.0%

The reactor system was programmed using Impressionist™ software (SymyxTechnologies, Inc., Santa Clara, CA) with the following array of volumes (derived froman experimental design array developed using Library Studio™ library design software(Symyx Technologies, Santa Clara, CA)) of each feed to add to each vessel, comprisingstarting materials for an emulsion polymer with targeted polymer content as a lineargradient from 20% polymer to 48% polymer, with constant ratios of 2.4% surfactantand 0.8% initiator to the amount of monomer, and an aim mass of 6.0 g of total materialadded to each of the eight vessels. The reactor was further programmed to add thefeeds to the reactor with the following feed profile:

Stage	Start time (s)	End time (s)	Number ofportions	Stage Description
1	0	1	1	Initial reactor charge
2	600	8400	200	Initiator addition
3	720	7920	200	Monomer addition

Feeds 1 and 2 (monomers) were programmed to all be added as a linear 120 minuteramp feed instage 3, with an allowable number of portions of 200, allowing individualadditions as small as 1/200 of the total requested volume, if permitted by hardware andexternal timing considerations. Feed 3 (water) was added entirely instage 1. Theinitial reactor charge components were allowed to stir and heat for 10 minutes beforeaddition of monomer or surfactant. Feed 4 (surfactant) was added 25% instage 1 and75% in stage 3). Feed 5 (initiator) was added instage 2, in a 130 minute ramp similartostage 3, but beginning two minutes earlier and ending eight minutes later. Thetemperature of the reactor was controlled at 80° C at the beginning of the reaction, withheating stopped to allow cooling to room temperature at 3.0 hours (10,800 seconds).The stirring rate was set to 900 rpm. The reactions were allowed to cool to < 50° Cbefore the stirring was stopped, the reactor opened, and the reaction products isolated.

Feed/Vessel	1,20%	2,24%	3,28%	4,32%	5,36%	6,40%	7,44%	8,48%
1, µL	1336.3	1603.6	1870.8	2138.1	2405.3	2672.6	2939.9	3207.1
2,µL	0	0	0	0	0	0	0	0
3, µL	4328.3	3978.1	3628.0	3277.8	2927.7	2577.5	2227.4	1877.2
4, µL	291.8	350.2	408.5	466.9	525.2	583.6	641.9	700.3
5, µL	243.2	291.8	340.4	389.1	437.7	486.3	535.0	583.6

Well-behaved, relatively low-viscosity emulsions were obtained, with little orno apparent skinning, drying, or coagulum formation. Average particle sizes of theemulsions were determined by dynamic light scattering, and percent solidsmeasurements were obtained by microwave drying of weighed samples, as shownbelow, demonstrating excellent emulsion quality and good agreement of theoreticalmeasured solids content for the emulsions.

Feed/Vessel	1	2	3	4	5	6	7	8
Particle radius,DLS, nm	32	32	35	31	32	40	37	42
% solids, theory	20.6	24.8	28.9	33.0	37.2	41.3	45.4	49.5
% solids,measured	20.7	25.2	29.0	32.6	37.6	41.4	44.7	49.2

In a similar manner, eight emulsion polymer samples utilizing all five feedswere prepared, adding styrene in place of 25% of the monomer mix, as in the followingtable.

Feed/Vessel	1,20%	2,24%	3,28%	4,32%	5,36%	6,40%	7,44%	8,48%
1, µL	1002.2	1202.7	1403.1	1603.6	1804.0	2004.5	2204,9	2405.3
2, µL	330.0	396.0	462.0	528.1	594.1	660.1	726.1	792.1
3, µL	4328.3	3978.1	3628.0	3277.8	2927.7	2577.5	2227.4	1877.2
4, µL	291.8	350.2	408.5	466.9	525.2	583.6	641.9	700.3
5, µL	243.2	291.8	340.4	389.1	437.7	486.3	535.0	583.6

The experiment was run in a manner substantially as described above.

In light of the detailed description of the invention and the examples presentedabove, it can be appreciated that the several objects of the invention are achieved.

The explanations and illustrations presented herein are intended to acquaintothers skilled in the art with the invention, its principles, and its practical application. Those skilled in the art may adapt and apply the invention in its numerous forms, asmay be best suited to the requirements of a particular use. Accordingly, the specificembodiments of the present invention as set forth are not intended as being exhaustiveor limiting of the invention.

Claims (76)

1. A parallel, semi-continuous or continuous, pressure reactorcomprising
   four or more semi-continuous or continuous reaction vessels forcontaining a liquid reaction mixture, each of the four or morereaction vessels being pressurizable to a pressure of not.lessthan about 50 psig,
   at least four liquid feed lines in selectable fluid communicationwith each of the four or more reaction vessels, each of the atleast four liquid feed lines being in fluid communication with oneor more liquid reagent source vessels, such that one or moreliquid reagents can be selectively fed from the one or moresource vessels to each of the four or more reaction vesselsduring a reaction under reaction conditions, and
   at least one feed-pressurization station pressurizable to apressure of not less than about 50 psig, at least a portion of eachof the at least four liquid feed lines being in selectable fluidcommunication with the at least one feed-pressurization station,such that the one or more liquid reagents prefeed to the feed-pressurizationstation under pressure to prepressurize the portionof the at least four liquid feed lines prior to feeding the one ormore liquid reagents to the four or more reaction vessels.
2. The parallel reactor of claim 1 wherein the feed-pressurizationstation is a waste vessel.
3. The parallel reactor of claim 1 further comprising four or moreshaft-driven impellers corresponding to the four or more reactionvessels for stirring the reaction mixtures.
4. The parallel reactor of claims 1 or 3 wherein each of the four ormore reaction vessels has a volume of not more than about 1liter.
5. The parallel reactor of claim 4 further comprising a reactor blockcontaining the four or more semi-continuous or continuousreaction vessels.
6. The parallel reactor of claims 1 through 5 wherein each of thefour or more reaction vessels is pressurizable to a pressure ofnot less than about 100 psig.
7. The parallel reactor of claim 5 wherein the at least four liquidfeed lines are provided to each of the four or more reactionvessels through one or more modular feed-line subassemblies,each of the feed-line subassemblies being adapted to releasablyengage the reactor block and to support at least two of the liquidfeed lines passing into the reaction vessel.
8. The parallel reactor of claim 7 wherein each of the one or moremodular feed-line subassemblies is a ferrule comprising two ormore apertures adapted to sealingly support the at least twoliquid feed lines when the ferrule is engaged with the reactorblock.
9. The parallel reactor of claims 5, 7 or 8 wherein the at least fourliquid feed lines are provided to each of the four or more reactionvessels through one or more ferrules,
   the reactor block further comprising four or more ferrule-receivingports each adapted to receive one of the ferrules, each of thereceiving ports being in fluid communication with one of thereaction vessels,
   each of the one or more ferrules comprising

   a first interior end for insertion into the correspondingreceiving port in the reactor block,

   a second exterior end substantially opposing the firstinterior end,

   four or more internal apertures extending from the firstinterior end to the second exterior end for supporting the atleast four liquid feed lines passing into one of the reactionvessels, the four or more internal apertures of the ferrulebeing adapted to sealingly support each of the at least fourliquid feed lines when the ferrule is engaged with thereceiving port,

   an external side surface including a tapered portion, thetapered portion having a smaller cross-section at positionscloser to the first interior end relative to positions fartherfrom the first interior end, the tapered portion beingconfigured to correspond to a tapered surface defining aportion of the receiving port, and

   a fastener for releasably connecting at least the taperedportion of the ferrule with the corresponding taperedsurface of the receiving port.
10. The parallel reactor of claims 1 through 9 wherein the at leastfour liquid feed lines are capillaries having an inside diameter ofnot more than about 1 mm.
11. The parallel reactor of claims 1 through 9 wherein the at leastfour liquid feed lines are capillaries having an outside diameter ofnot more than about 1 mm.
12. The parallel reactor of claims 1 through 9 wherein the at leastfour liquid feed lines are fused silica capillaries.
13. The parallel reactor of claims 1 through 9 wherein the at leastfour liquid feed lines are stainless steel capillaries.
14. The parallel reactor of claims 1 through 9 wherein the at leastfour liquid feed lines are polymer capillaries.
15. The parallel reactor of claims 5 or 7 through 9 wherein each ofthe four or more reaction vessels is defined by or contained in alower portion of a reaction cavity in the reactor block, thereaction cavity being further defined by an upper portion in thereactor block, the upper portion of the reaction cavity having alarger cross section, taken radially, relative to the lower portion,such that two or more of the at least four liquid feed lines can bepassed through the upper portion to the lower portion of thereaction cavity.
16. The parallel reactor of claim 15 wherein the lower portion of thereaction cavity has a substantially circular cross section, takenradially, and the upper portion of the reaction cavity has asubstantially oval cross section, taken radially.
17. The parallel reactor of claims 5, 7 through 9, 15 or 16 whereineach of the four or more reaction vessels is defined by or contained in a reaction cavity in the reactor block, the reactioncavity having a substantially uniform cross section, takenradially.
18. The parallel reactor of claim 17 wherein the reaction cavity is acylindrical reaction cavity.
19. The parallel reactor of claims 1 through 17 wherein the at leastfour liquid feed lines in fluid communication with each of the fouror more reaction vessels comprises at least a first section and asecond section in fluid communication with each other, thesecond section being releasably connected with the first sectionand having a distal end positioned within the reaction vessel.
20. The parallel reactor of claim 19 wherein the first section ispositioned such that it is outside of the reaction vessel, andadditionally or alternatively, at least substantially uncontaminatedby the liquid reaction mixture.
21. The parallel reactor of claim 19 wherein the first section ispositioned such that at least a portion thereof is inside a reactioncavity that contains or defines the reaction vessel.
22. The parallel reactor of claim 19 wherein the first section is apolymer capillary and the second section is a stainless steelcapillary.
23. The parallel reactor of claims 1 through 22 wherein each of the atleast four liquid feed lines has a distal end positioned within thereaction vessel, the distal end of one or more of the liquid feedlines being positioned lower in the reaction vessel relative to thedistal end of one or more other of the liquid feed lines.
24. The parallel reactor of claim 23 wherein the distal end of one ormore of the liquid feed lines is positioned in the reaction vesselto terminate in the liquid reaction mixture such that feed isdelivered through such one or more liquid feed lines directly intothe liquid reaction mixture, and
    the distal end of one or more other of the liquid feed lines. ispositioned in the reaction vessel such that feed is deliveredthrough such one or more other liquid feed lines into a gaseousheadspace above the liquid reaction mixture.
25. The parallel reactor of claim 1 through 24 wherein the insidediameter or cross-sectional flow area for one or more of the atleast four liquid feed lines is different from the inside diameter orcross-sectional flow area for another of the at least four liquidfeed lines.
26. The parallel reactor of claims 1 through 18 further comprising aparallel feed-line interface providing fluid communicationbetween a first section and a second section of each of the atleast four liquid feed lines, the interface being releasablyconnected to the first section and additionally or alternatively, tothe second section, of each of the at least four liquid feed lines.
27. The parallel reactor of claims 1 through 25 wherein at least oneliquid feed line for each of the four or more reaction vessels is indirect fluid communication with one of the one or more liquidreagent source vessels.
28. The parallel reactor of claims 1 through 25 further comprising atleast one feed distribution valve providing selective fluidcommunication between the one or more liquid reagent sourcevessels and at least one liquid feed line for each of the four ormore reaction vessels.
29. The parallel reactor of claims 1 through 25 further comprising atleast one syringe-type feed pump for feeding one or more liquidreagents from one or more source vessels through one or moreof the liquid feed lines to the selected one or more reactionvessels.
30. The parallel reactor of claims 1 through 29 further comprisingfour or more gas ports, each of the four or more gas portsproviding fluid communication to one of the four or more reactionvessels.
31. The parallel reactor of claims 1 through 29 further comprisingfour or more pairs of gas ports, each of the pairs of gas portsproviding fluid communication with one of the four or morereaction vessels.
32. The parallel reactor of claim 30 wherein each of the four or morethe gas ports is a gaseous feed port, a pressure monitoring port,a pressure control port or a gaseous purge port.
33. The parallel reactor of claims 1 through [39]32 further comprisingfour or more discharge lines, each of the four or more dischargelines providing fluid communication to one of the four or morereaction vessels.
34. The parallel reactor of claims 5, 7 through 9 or 15 through 18wherein the four or more reaction vessels comprise wells formedin the reactor block.
35. The parallel reactor of claims 5, 7 through 9 or 15 through 18wherein the four or more reaction vessels are removable linerssupported by wells formed in the reactor block, each of the liners having an interior surface defining a cavity for containing one ofthe liquid reaction mixtures, and an external surface dimensionedto fit within the wells.
36. The parallel reactor of claim 35 wherein the removable liners areglass vials.
37. The parallel reactor of claims 1 through 36 wherein each of thefour or more reaction vessels has an aspect ratio (L/D) of at leastabout 1.5.
38. The parallel reactor of claim 37 wherein each of the four or morereaction vessels has an aspect ratio (L/D) of at least about 2.
39. The parallel reactor of claims 5, 7 through 9, 15 through 18, 34 or35 wherein the reactor block comprises a base block comprisingfour or more wells defining or containing the four or morereaction vessels, and a header block positioned on the baseblock to form four or more pressurizable reaction cavities, eachof the four or more reaction cavities defining or containing one ofthe four or more reaction vessels.
40. The parallel reactor of claim 39 wherein the header blockcomprises the four or more shaft-driven impellers.
41. The parallel reactor of claim 40 further comprising a disposableheader gasket situated between the base block and the headerblock, the disposable header gasket including four or moremasking regions corresponding to the four or more reactioncavities, each of the four or more masking regions being adaptedto mask the portion of the header block exposed to the reactioncavity.
42. The parallel reactor of claims 3 or 40 further comprising four ormore disposable shaft covers corresponding to the four or moreshaft-driven impellers, each of the four or more shaft coversbeing adapted to mask at least a non-disposable portion of ashaft of the shaft-driven impeller exposed to the reaction cavity.
43. The parallel reactor of claim 5 wherein the reactor blockcomprises a base block comprising
    four or more wells defining or containing the four or morereaction vessels, and
    a header block positioned on the base block to form four or morepressurizable reaction cavities, each of the four or more reactioncavities defining or containing one of the four or more reactionvessels, the header block further comprising four or more feed-linesubassembly receiving ports, each adapted to receive one ofthe modular feed-line subassemblies.
44. The parallel reactor of claims 1 through 43 wherein each of thefour or more reaction vessels has a volume of not more thanabout 500 ml.
45. The parallel reactor of claim 44 wherein each of the four or morereaction vessels has a volume ranging from about 1 ml to about100 ml.
46. The parallel reactor of claims 1 through 45 wherein each of thefour or more reaction vessels is pressurizable to a pressure ofnot less than about 400 psig.
47. The parallel reactor of claim 46 wherein each of the four or morereaction vessels is pressurizable to a pressure ranging fromabout 500 psig to about 1500 psig.
48. The parallel reactor of claims 5, 7 through 9, 15 through 18, 34,35, 39 or 43 wherein the reactor block further comprises one ormore temperature control elements for individual or modulartemperature control of the four or more reaction vessels.
49. The parallel reactor of one of the preceding claims, comprising
    four or more semi-continuous or continuous reaction vessels forcontaining a liquid reaction mixture, each of the four or morereaction vessels having a volume of not more than about 1 liter,
    at least four liquid feed lines in selectable fluid communicationwith each of the four or more reaction vessels, each of the atleast four liquid feed lines being in fluid communication with oneor more liquid reagent source vessels, four or more modularfeed-line subassemblies, each of the four or more feed-linesubassemblies being adapted to releasably engage one of thefour or more reaction vessels or a reactor block that defines orcontains the reaction vessels, each of the feed-linesubassemblies supporting two or more of the at least four liquidfeed lines, and providing the two or more liquid feed lines to thereaction vessels through a feed-line subassembly receiving portformed in the reaction vessel or the reactor block.
50. A parallel reactor of one of the preceding claims, comprising
    four or more semi-continuous or continuous reaction vessels forcontaining a liquid reaction mixture, each of the four or morereaction vessels having a volume of not more than about 1 liter,
    at least four liquid feed lines in selectable fluid communicationwith each of the four or more reaction vessels, each of the atleast four liquid feed lines being in fluid communication with one or more liquid reagent source vessels, each of the at least fourliquid feed lines comprising at least a first section and a secondsection in fluid communication with each other, the secondsection being releasably connected with the first section andhaving a distal end positioned within one of the reaction vessels.
51. The parallel reactor of one of the preceding claims, comprising
    four or more semi-continuous or continuous reaction vessels forcontaining a liquid reaction mixture, each of the four or morereaction vessels having a volume of not more than about 1 liter,
    at least four liquid feed lines in selectable fluid communicationwith each of the four or more reaction vessels, each of the atleast four liquid feed lines being in fluid communication with oneor more liquid reagent source vessels, each, of the at least fourliquid feed lines having a distal end positioned within the reactionvessel, the distal end of one or more of the liquid feed lines beingpositioned lower in the reaction vessel relative to the distal endof one or more other of the liquid feed lines.
52. The parallel reactor of one of the preceding claims, comprising
    four or more semi-continuous or continuous reaction vessels forcontaining a liquid reaction mixture, each of the four or morereaction vessels having a volume of not more than about 1 liter,
    at least four liquid feed lines in selectable fluid communicationwith each of the four or more reaction vessels, each of the atleast four liquid feed lines being in fluid communication with oneor more liquid reagent source vessels, one or more of the at leastfour liquid feed lines having an inside diameter or cross-sectionalflow area that differs from the inside diameter or cross-sectionalflow area for another of the at least four liquid feed lines.
53. The parallel reactor of claims 49, 50, 51 or 52 further comprisingfour or more shaft-driven impellers corresponding to the four ormore reaction vessels for stirring the reaction mixtures.
54. The reactor of claims 49, 50, 51 or 52 wherein the four or morereaction vessels are semi-continuous flow reaction vessels.
55. The parallel reactor of claims 49, 50, 51 or 52 wherein the four ormore reaction vessels are continuous flow reaction vessels
56. The parallel reactor of claim 49, 50, 51 or 52 wherein the four ormore reaction vessels are removable liners supported by a wellformed in a reactor block, the liners having an interior surfacedefining a cavity for containing the liquid reaction mixture, and anexternal surface dimensioned to fit within the well.
57. The parallel reactor of claim 49, 50, 51 or 52 wherein the four ormore reaction vessels are formed in a reactor block, the reactorblock further comprising one or more temperature controlelements for individual or modular temperature control of the fouror more reaction vessels.
58. The parallel reactor of claim 49, 50, 51 or 52 wherein each of thefour or more reaction vessels is hermetically sealable.
59. The parallel reactor of claim 49, 50, 51 or 52 wherein each of thefour or more reaction vessels is pressurizable to a pressure ofnot less than about 50 psig.
60. A method for effecting chemical reactions in parallel, the methodcomprising
    providing the parallel reactor of claims 1, 49, 50, 51 or 52, and feeding four or more liquid reagents through the four or moreliquid feed lines to each of the four or more reactors during thecourse of a reaction.
61. A method for effecting chemical reactions in parallel in a parallel,semicontinuous or continuous, pressure reactor, the methodcomprising
    providing a parallel pressure reactor, the reactor comprising fouror more semicontinuous or continuous reaction vessels, one ormore liquid reagent source vessels, and at least four liquid feedlines providing selectable fluid communication between the oneor more liquid reagent source vessels and the four or morereaction vessels,
    initiating a chemical reaction in each of the four or more reactionvessels under reaction conditions that include a reactionpressure of not less than about 50 psig,
    prefeeding the one or more liquid reagents through at least aportion of one or more of the at least four liquid feed lines to afeed-pressurization zone, the feed-pressurization zone beingmaintained at a pressure of not less than about 50 psig, suchthat at least a portion of the one or more of the at least four liquidfeed lines contain prepressurized liquid reagent feed, and
    feeding the prepressurized liquid reagent feed into a downstreamfeed zone or into one or more of the four or more reactionvessels during the reaction under the reaction conditions.
62. A method for effecting chemical reactions in parallel in a parallel,semicontinuous or continuous reactor, the method comprising
    providing a parallel reactor, the reactor comprising four or moresemicontinuous or continuous reaction vessels, four or moreliquid reagent source vessels, and at least four liquid feed linesproviding selectable fluid communication between the four ormore liquid reagent source vessels and the four or more reactionvessels,
    initiating a chemical reaction in each of the four or more reactionvessels under reaction conditions,
    feeding the four or more liquid reagents into the four or morereaction vessels during the reaction under the reactionconditions, and
    controlling, for each of the reaction vessels,

    a total volume of each of the liquid reagents being fed tothe reaction vessel during the reaction, the total volumebeing the same or different as compared between differentreagents,

    a number of stages in which the total volume for each ofthe liquid reagents is fed to the reaction vessel during thereaction, the number of stages being the same or differentas compared between different reagents,

    a stage volume defined by a percentage of the totalvolume associated with each of the stages for each of theliquid reagents, the stage volume being the same ordifferent as compared between different stages for each ofthe liquid reagents,

    a feed sequence defined by a relative order in which thestages for each of the liquid reagents is fed to the reactionvessel during the reaction, and

    a temporal profile associated with feed addition to thereaction vessel for each of the stages for each of the liquidreagents, the temporal profile being defined for each stageby a number of feed increments in which the stage volumeis added to the reaction vessel, and the period of time inwhich the stage volume is added to the reaction vessel.
63. The method of claim 62 wherein the number of stages in whichthe total volume for each of the liquid reagents is fed to thereaction vessel during the reaction is at least two stages.
64. The method of claims 62 or 63 wherein the number of feedincrements in which the stage volume is added to the reactionvessel is at least two feed increments.
65. The method of claim 62 further comprising controlling theflowrate for each feed increment added to the reaction vessel.
66. The method of claim 62 wherein the feed addition is controlled,between reaction vessels, sequentially, on a rotating basis, foreach of the four or more reaction vessels during the reaction by

    (i) considering and providing the feed requirements for a firstreaction vessel at a first time after initiation of the chemicalreaction therein, and thereafter,

    (ii) by considering and providing the feed requirements for asecond reaction vessel at a second time after initiation ofthe chemical reaction therein, and thereafter,

    (iii) by considering and providing the feed requirements for athird reaction vessel at a third time after initiation of thechemical reaction therein, and thereafter,

    (iv) by considering and providing the feed requirements for afourth reaction vessel at a fourth time after initiation of thechemical reaction therein.
67. The method of claim 66 wherein the feed addition is furthercontrolled for each of the four or more reaction vessels duringthe reaction by

    (v) reconsidering and providing additional feed requirementsfor the first reaction vessel at a fifth time after initiation ofthe chemical reaction therein, the fifth time being a timelater than the first time, and thereafter,

    (vi) by reconsidering and providing additional feedrequirements for the second reaction vessel at a sixth timeafter initiation of the chemical reaction therein, the sixthtime being a time later than the second time, andthereafter,

    (vii) by reconsidering and providing additional feedrequirements for the third reaction vessel at a seventh timeafter initiation of the chemical reaction therein, the seventhtime being a time later than the third time, and thereafter,

    (iv) by reconsidering and providing additional feedrequirements for the fourth reaction vessel at a eighth timeafter initiation of the chemical reaction therein, the eighthtime being a time later than the fourth time.
68. The method of claim 66 wherein the sequential control is effectedfrom a per reaction-vessel framework, defined by providing all ofthe feed requirements for a particular reaction vessel at theparticular time, from each of the at least four liquid feed lines,before providing the feed requirements for the next particularreaction vessel at the next particular time from any of the at leastfour liquid feed lines.
69. The method of claim 66 wherein the sequential control is effectedfrom a per feed-line framework, defined by controlling andproviding the feed requirements for a particular reaction vessel atthe particular time from one of the at least four liquid feed linesindependent from other liquid feed lines of the at least four feedlines.
70. The method of claim 66 wherein the step of considering the feedrequirements includes determining the feed requirements for aparticular reaction vessel for a particular time by reference to afeed recipe specifying the required feed versus the time ofreaction for each of the four or more liquid reactions for each ofthe four or more reaction vessels.
71. The method of claim 66 wherein the step of considering the feedrequirements includes determining the feed requirements for aparticular reaction vessel for a particular time by reference to adetermined value from a feedback control system.
72. The method of claim 66 wherein sequence of control is advancedfrom one reaction vessel to the next reaction vessel at regular,recurring time intervals.
73. The method of claim 66 wherein sequence of control is advancedfrom one reaction vessel to the next reaction vessel after all of the feed requirements for the one reaction vessel have beenprovided for the particular time for the particular reaction vessel.
74. The method of claim 66 wherein the chemical reactions aresequentially initiated in the four or more reaction vessels.
75. The method of claim 66 wherein the chemical reactions aresequentially initiated in the four or more reaction vessels, suchthat the time elapsed between reaction initiation and the first,second, third and fourth times at which the feed requirements forthe first, second, third and fourth reaction vessels, respectively,are considered and provided, are substantially the same ascompared between reaction vessels.
76. The method of claim 66 wherein the chemical reactions areinitiated in the four or more reaction vessels at substantially thesame time.

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